U.S. patent application number 10/264764 was filed with the patent office on 2003-07-31 for alkyne matrix metalloproteinase inhibitors.
Invention is credited to Bunker, Amy Mae, Harter, William Glen, Hicks, James Lester, O'Brien, Patrick Michael, Pham, Ly, Picard, Joseph Armand, Roark, William Howard.
Application Number | 20030144274 10/264764 |
Document ID | / |
Family ID | 23284384 |
Filed Date | 2003-07-31 |
United States Patent
Application |
20030144274 |
Kind Code |
A1 |
Bunker, Amy Mae ; et
al. |
July 31, 2003 |
Alkyne matrix metalloproteinase inhibitors
Abstract
A compound of Formula I 1 or a pharmaceutically acceptable salt
thereof, or a tautomer thereof, wherein G.sub.1, G.sub.2, and B are
as defined in the application, are selective inhibitors of MMP-13.
The compounds are useful for treating diseases mediated by MMP-13,
including cancer and arthritis.
Inventors: |
Bunker, Amy Mae; (Ann Arbor,
MI) ; Harter, William Glen; (Chelsea, MI) ;
Hicks, James Lester; (Chelsea, MI) ; O'Brien, Patrick
Michael; (Stockbridge, MI) ; Pham, Ly; (Ann
Arbor, MI) ; Picard, Joseph Armand; (Canton, MI)
; Roark, William Howard; (Ann Arbor, MI) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Family ID: |
23284384 |
Appl. No.: |
10/264764 |
Filed: |
October 4, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60329216 |
Oct 12, 2001 |
|
|
|
Current U.S.
Class: |
514/223.2 ;
514/222.8; 514/256; 514/300; 514/312; 514/336; 544/10; 544/11;
544/12; 544/333; 546/113; 546/153; 546/268.1 |
Current CPC
Class: |
A61P 11/00 20180101;
C07C 255/57 20130101; C07D 213/56 20130101; A61P 17/06 20180101;
A61P 29/00 20180101; C07C 235/42 20130101; C07C 317/32 20130101;
C07D 233/56 20130101; C07D 249/08 20130101; A61P 19/02 20180101;
A61P 1/00 20180101; A61P 35/00 20180101; C07D 213/64 20130101; A61P
9/04 20180101; C07D 231/12 20130101; C07D 279/02 20130101; C07D
513/04 20130101; C07C 311/46 20130101; A61P 1/02 20180101; C07D
213/82 20130101; C07D 515/04 20130101; C07D 401/06 20130101; A61P
19/10 20180101; C07D 213/81 20130101; A61P 17/00 20180101; C07D
249/04 20130101; A61P 9/10 20180101; C07D 215/233 20130101; A61P
43/00 20180101; C07D 285/16 20130101; C07D 285/24 20130101; C07D
495/04 20130101; A61P 11/06 20180101; C07D 213/40 20130101; C07C
233/87 20130101; A61P 19/08 20180101; C07C 255/60 20130101; C07D
291/08 20130101 |
Class at
Publication: |
514/223.2 ;
514/222.8; 514/256; 514/336; 514/312; 514/300; 544/10; 544/11;
544/12; 544/333; 546/113; 546/153; 546/268.1 |
International
Class: |
C07D 285/16; C07D
471/02; A61K 031/549 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 2, 2002 |
PCT/IB02/03057 |
Claims
What is claimed is:
1. A compound of Formula I 87or a pharmaceutically acceptable salt
thereof, or a tautomer thereof, wherein: G.sub.1 and G.sub.2
independently are 88wherein E is independently O or S; A is
OR.sub.1 or NR.sub.1R.sub.2; R.sub.1 and R.sub.2 independently are
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, (CH.sub.2).sub.naryl, or
(CH.sub.2).sub.ncycloalkyl, (CH.sub.2).sub.nheteroaryl, or R.sub.1
and R.sub.2 are taken together with the nitrogen atom to which they
are attached to complete a 3- to 8-membered ring having carbon
atoms, the nitrogen atom bearing R.sub.1 and R.sub.2, and 0 or 1
heteroatom selected from N(H), N(CH.sub.3), O, and S, and which
ring is optionally unsubstituted or substituted with .dbd.O, halo,
or methyl, wherein n is an integer of from 0 to 6; or G.sub.1 and
G.sub.2 independently are hydrogen, halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
(CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4; m is an integer of from 0
to 6; q is an integer of 0 or 1; R.sub.3 and R.sub.4 independently
are hydrogen, C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; B is: 8990wherein: each Y is
independently O or S; R.sub.5, R.sub.6, and R.sub.7 independently
are hydrogen, halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, NO.sub.2,
NR.sub.9R.sub.10, CN, or CF.sub.3, wherein R.sub.9 and R.sub.10
independently are hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken
together with the nitrogen atom to which they are attached to form
a 3- to 7-membered ring having carbon atoms, the nitrogen atom
bearing R.sub.9 and R.sub.10, and 0 or 1 atoms selected from O, S,
N(H), and N(CH.sub.3); R.sub.8 is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
CH.sub.2CO.sub.2H, OH, NH.sub.2, or C.sub.1-C.sub.6 alkanoyl; X is
S, S(O), S(O).sub.2, O, N(R.sub.8), wherein R.sub.8 is as defined
above, C(.dbd.O), or CH.sub.2; and -- is a bond or is absent.
2. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, wherein: G.sub.1
and G.sub.2 independently are (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl, or
(CH.sub.2).sub.msubstituted heteroaryl, wherein m is an integer of
from 0 to 6 and aryl, substituted aryl, heteroaryl, and substituted
heteroaryl are as defined in claim 1.
3. A compound of Formula II 91or a pharmaceutically acceptable salt
thereof, or a tautomer thereof, wherein: G.sub.1 and G.sub.2
independently are 92wherein E is independently O or S; A is
OR.sub.1 or NR.sub.1R.sub.2; R.sub.1 and R.sub.2 independently are
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, (CH.sub.2).sub.naryl,
(CH.sub.2).sub.ncycloalkyl, or (CH.sub.2).sub.nheteroaryl, or
R.sub.1 and R.sub.2 are taken together with the nitrogen atom to
which they are attached to complete a 3- to 8-membered ring having
carbon atoms, the nitrogen atom bearing R.sub.1 and R.sub.2, and 0
or 1 heteroatom selected from N(H), N(CH.sub.3), O, and S, and
which ring is optionally unsubstituted or substituted with .dbd.O,
halo, or methyl, wherein n is an integer of from 0 to 6; or G.sub.1
and G.sub.2 independently are hydrogen, halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
(CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4; m is an integer of from 0
to 6; q is an integer of 0 or 1; R.sub.3 and R.sub.4 independently
are hydrogen, C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; and R.sub.5, R.sub.6, and R.sub.7
independently are hydrogen, halo, hydroxy, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, NO.sub.2, CN, CF.sub.3, or NR.sub.9R.sub.10, wherein
R.sub.9 and R.sub.10 independently are hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.7 cycloalkyl, phenyl, or benzyl, or R.sub.9
and R.sub.10 are taken together with the nitrogen atom to which
they are attached to complete a 3- to 7-membered ring having carbon
atoms, the nitrogen atom bearing R.sub.9 and R.sub.10, and 0 or 1
heteroatoms selected from N(H), N(CH.sub.3), O, and S.
4. The compound according to claim 3, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, wherein: G.sub.1
and G.sub.2 independently are (CH.sub.2).sub.maryl, wherein m is 1
and aryl is phenyl, (CH.sub.2).sub.msubstituted aryl, wherein m is
1 and substituted aryl is 4-methoxyphenyl, 3-methoxyphenyl,
4-fluorophenyl, 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl,
4-bromophenyl, 3-bromophenyl, 4-nitrophenyl, 3-nitrophenyl,
4-methylsulfanylphenyl, 3-methylsulfanylphenyl, 4-methylphenyl,
3-methylphenyl, 4-cyanophenyl, 3-cyanophenyl, 4-carboxyphenyl,
3-carboxyphenyl, 4-methanesulfonylphenyl, or
3-methanesulfonylphenyl, (CH.sub.2).sub.mheteroaryl, wherein m is 1
and heteroaryl is pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl, or
(CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl; and R.sub.5,
R.sub.6, and R.sub.8 are hydrogen.
5. The compound according to claim 3, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, selected from:
3-(4-Methoxy-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(4-methoxy-phenyl)-prop-1-ynyl)-benzamide;
3-(3-Methoxy-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-methoxy-phenyl)-prop-1-ynyl)-benzamide;
3-(4-Cyano-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(4-cyano-phenyl)-prop-1-ynyl)-benzamide;
3-(3-Cyano-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-cyano-phenyl)-prop-1-ynyl)-benzamide;
3-(4-Fluoro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(4-fluoro-phenyl)-prop-1-ynyl)-benzamide;
3-(3-Fluoro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-fluoro-phenyl)-prop-1-ynyl)-benzamide;
3-(4-Chloro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(4-chloro-phenyl)-prop-1-ynyl)-benzamide;
3-(3-Chloro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-chloro-phenyl)-prop-1-ynyl)-benzamide;
3-(4-Bromo-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(4-bromo-phenyl)-prop-1-ynyl)-benzamide;
3-(3-Bromo-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-bromo-phenyl)-prop-1-ynyl)-benzamide;
3-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(4-methanesulfanyl-phenyl)-prop-1-ynyl)-be-
nzamide;
3-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-ben-
zamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-methanesulfanyl-phenyl)-prop-1-y-
nyl)-benzamide;
3-(4-Methyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benza- mide;
N-(4-Methanesulfonyl-benzyl)-3-(4-methyl-phenyl)-prop-1-ynyl)-benzam-
ide;
3-(3-Methyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-methyl-phenyl)-prop-1-ynyl)-benzamide;
3-(3-Pyridin-4-yl-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-pyridin-4-yl-prop-1-ynyl)-benzamide;
3-(3-Pyridin-3-yl-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-pyridin-3-yl-prop-1-ynyl)-benzamide;
3-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-N-(4-carboxybenzyl)-benzamide;
and
N-(4-Methanesulfonyl-benzyl)-3-[3-(2-methoxy-pyridin-4-yl)-prop-1-yny-
l]-benzamide.
6. A compound of Formula III 93or a pharmaceutically acceptable
salt thereof, or a tautomer thereof, wherein: G.sub.1 and G.sub.2
independently are 94wherein E is independently O or S; A is
OR.sub.1 or NR.sub.1R.sub.2; R.sub.1 and R.sub.2 independently are
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, (CH.sub.2).sub.naryl,
(CH.sub.2).sub.ncycloalkyl, or (CH.sub.2).sub.nheteroaryl, or
R.sub.1 and R.sub.2 are taken together with the nitrogen atom to
which they are attached to complete a 3- to 8-membered ring having
carbon atoms, the nitrogen atom bearing R.sub.1 and R.sub.2, and 0
or 1 heteroatom selected from N(H), N(CH.sub.3), O, and S, and
which ring is optionally unsubstituted or substituted with .dbd.O,
halo, or methyl, wherein: n is an integer of from 0 to 6; or
G.sub.1 and G.sub.2 independently are hydrogen, halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4; m is an integer of from 0
to 6; q is an integer of 0 or 1; R.sub.3 and R.sub.4 independently
are hydrogen, C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; and R.sub.5 and R.sub.6
independently are hydrogen, halo, hydroxy, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, NO.sub.2, CN, CF.sub.3, or NR.sub.9R.sub.10, wherein
R.sub.9 and R.sub.10 independently are hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.7 cycloalkyl, phenyl, or benzyl, or R.sub.9
and R.sub.10 are taken together with the nitrogen atom to which
they are attached to complete a 3- to 7-membered ring having carbon
atoms, the nitrogen atom bearing R.sub.9 and R.sub.10, and 0 or 1
atoms selected from N(H), N(CH.sub.3), O, and S.
7. The compound according to claim 6, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, wherein: G.sub.1
and G.sub.2 independently are (CH.sub.2).sub.maryl, wherein m is 1
and aryl is phenyl, (CH.sub.2).sub.msubstituted aryl, wherein m is
1 and substituted aryl is 4-methoxyphenyl, 3-methoxy phenyl,
4-fluorophenyl, 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl,
4-bromophenyl, 3-bromophenyl, 4-nitrophenyl, 3-nitrophenyl,
4-methylsulfanylphenyl, 3-methylsulfanylphenyl, 4-methylphenyl,
3-methylphenyl, 4-cyanophenyl, 3-cyanophenyl, 4-carboxyphenyl,
3-carboxyphenyl, 4-methanesulfonylphenyl, or
3-methanesulfonylphenyl, (CH.sub.2).sub.mheteroaryl, wherein m is 1
and heteroaryl is pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl, or
(CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl; and R.sub.5 and
R.sub.6, are hydrogen.
8. The compound according to claim 6, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, selected from:
3-(4-Methoxy-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamide;
N-(4-Methanesulfonyl-benzyl)-3-(4-methoxy-phenyl)-prop-1-ynyl)-isonicotin-
amide;
3-(3-Methoxy-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinami-
de;
N-(4-Methanesulfonyl-benzyl)-3-(3-methoxy-phenyl)-prop-1-ynyl)-isonico-
tinamide;
3-(4-Cyano-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinam-
ide;
N-(4-Methanesulfonyl-benzyl)-3-(4-cyano-phenyl)-prop-1-ynyl)-isonicot-
inamide;
3-(3-Cyano-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinami-
de;
N-(4-Methanesulfonyl-benzyl)-3-(3-cyano-phenyl)-prop-1-ynyl)-isonicoti-
namide;
3-(4-Fluoro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinami-
de;
N-(4-Methanesulfonyl-benzyl)-3-(4-fluoro-phenyl)-prop-1-ynyl)-isonicot-
inamide;
3-(3-Fluoro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinam-
ide;
N-(4-Methanesulfonyl-benzyl)-3-(3-fluoro-phenyl)-prop-1-ynyl)-isonico-
tinamide;
3-(4-Chloro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotina-
mide;
N-(4-Methanesulfonyl-benzyl)-3-(4-chloro-phenyl)-prop-1-ynyl)-isonic-
otinamide;
3-(3-Chloro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotin-
amide;
N-(4-Methanesulfonyl-benzyl)-3-(3-chloro-phenyl)-prop-1-ynyl)-isoni-
cotinamide;
3-(4-Bromo-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotin-
amide;
N-(4-Methanesulfonyl-benzyl)-3-(4-bromo-phenyl)-prop-1-ynyl)-isonic-
otinamide;
3-(3-Bromo-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotina-
mide;
N-(4-Methanesulfonyl-benzyl)-3-(3-bromo-phenyl)-prop-1-ynyl)-isonico-
tinamide;
3-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-is-
onicotinamide;
N-(4-Methanesulfonyl-benzyl)-3-(4-methanesulfanyl-phenyl)-p-
rop-1-ynyl)-isonicotinamide;
3-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-N-(-
4-carboxybenzyl)-isonicotinamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-methan-
esulfanyl-phenyl)-prop-1-ynyl)-isonicotinamide;
3-(4-Methyl-phenyl)-prop-1-
-ynyl)-N-(4-carboxybenzyl)-isonicotinamide;
N-(4-Methanesulfonyl-benzyl)-3-
-(4-methyl-phenyl)-prop-1-ynyl)-isonicotinamide;
3-(3-Methyl-phenyl)-prop--
1-ynyl)-N-(4-carboxybenzyl)-isonicotinamide;
N-(4-Methanesulfonyl-benzyl)--
3-(3-methyl-phenyl)-prop-1-ynyl)-isonicotinamide;
3-(3-Pyridin-4-yl-prop-1-
-ynyl)-N-(4-carboxybenzyl)-isonicotinamide;
N-(4-Methanesulfonyl-benzyl)-3-
-(3-pyridin-4-yl-prop-1-ynyl)-isonicotinamide;
3-(3-Pyridin-3-yl-prop-1-yn-
yl)-N-(4-carboxybenzyl)-isonicotinamide;
N-(4-Methanesulfonyl-benzyl)-3-(3-
-pyridin-3-yl-prop-1-ynyl)-isonicotinamide;
3-[3-(2-Methoxy-pyridin-4-yl)--
prop-1-ynyl]-N-(4-carboxybenzyl)-isonicotinamide; and
N-(4-Methanesulfonyl-benzyl)-3-[3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl]-i-
sonicotinamide.
9. A compound of Formula IV 95or a pharmaceutically acceptable salt
thereof, or a tautomer thereof, wherein: G.sub.1 and G.sub.2
independently are 96wherein E is independently O or S; A is
OR.sub.1 or NR.sub.1R.sub.2; R.sub.1 and R.sub.2 independently are
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, (CH.sub.2).sub.naryl,
(CH.sub.2).sub.ncycloalkyl, or (CH.sub.2).sub.nheteroaryl, or
R.sub.1 and R.sub.2 are taken together with the nitrogen atom to
which they are attached to complete a 3- to 8-membered ring having
carbon atoms, the nitrogen atom bearing R.sub.1 and R.sub.2, and 0
or 1 heteroatom selected from N(H), N(CH.sub.3), O, and S, and
which ring is optionally unsubstituted or substituted with .dbd.O,
halo, or methyl, wherein n is an integer of from 0 to 6; or G.sub.1
and G.sub.2 independently are hydrogen, halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
(CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4; m is an integer of from 0
to 6; q is an integer of 0 or 1; R.sub.3 and R.sub.4 independently
are hydrogen, C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; Y is independently O or S;
R.sub.5, R.sub.6, and R.sub.7 independently are hydrogen, halo,
hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, NO.sub.2, CN,
CF.sub.3, or NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10
independently are hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.9 and R.sub.10, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; and R.sub.8 is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
CH.sub.2CO.sub.2H, NH.sub.2, or OH.
10. The compound according to claim 9, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof: wherein: Y is 0;
G.sub.1 and G.sub.2 independently are (CH.sub.2).sub.maryl, wherein
m is 1 and aryl is phenyl, (CH.sub.2).sub.msubstituted aryl,
wherein m is 1 and substituted aryl is 4-methoxyphenyl,
3-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-chlorophenyl,
3-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-nitrophenyl,
3-nitrophenyl, 4-methylsulfanylphenyl, 3-methylsulfanylphenyl,
4-methylphenyl, 3-methylphenyl, 4-cyanophenyl, 3-cyanophenyl,
4-carboxyphenyl, 3-carboxyphenyl, 4-methanesulfonylphenyl, or
3-methanesulfonylphenyl, (CH.sub.2).sub.mheteroaryl, wherein m is 1
and heteroaryl is piperidin-1-yl, piperazin-1-yl,
tetrahydrofuran-2-yl, pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl,
or (CH.sub.2).sub.msubstitut- ed heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl,
(CH.sub.2).sub.mcycloalkyl, wherein m is 1 and cycloalkyl is
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;
and R.sub.8 is hydrogen or methyl.
11. The compound according to claim 9, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, selected from:
2-Benzyl-4-methyl-1,1-dioxo-7-(3-phenyl
-prop-1-ynyl)-1,4-dihydro-2H-1l.s-
up.6-benzo[1,2,4]thiadiazin-3-one;
4-[4-Methyl-1,1,3-trioxo-7-(3-phenyl-pr-
op-1-ynyl)-3,4-dihydro-1H-1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benz-
oic acid; 2-Benzyl-1,1-dioxo-7-(3-phenyl-prop-1-ynyl)- i
,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one;
4-[1,1,3-Trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1l.sup.6-benzo[1,-
2,4]thiadiazin-2-ylmethyl]-benzoic acid;
2-Benzyl-4-methyl-1,1-dioxo-7-[3--
(4-methoxyphenyl)-prop-1-ynyl]-1,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadia-
zin-3-one;
2-Benzyl-1,1-dioxo-7-[3-(4-methoxyphenyl)-prop-1-ynyl]-1,4-dihy-
dro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one;
4-{1,1,3-Trioxo-7-[3-(4-meth- oxyphenyl)-prop-1-ynyl]-4-methyl
-3,4-dihydro-1H-1l.sup.6-benzo[1,2,4]thia-
diazin-2-ylmethyl}-benzoic acid;
4-{1,1,3-Trioxo-7-[3-(4-methoxyphenyl)-pr-
op-1-ynyl]-3,4-dihydro-1H-1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl}-benz-
oic acid;
2-Benzyl-4-methyl-1,1-dioxo-7-[3-(3-methoxyphenyl)-prop-1-ynyl]--
1,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one;
2-Benzyl-1,1-dioxo-7-[3-(3-methoxyphenyl)-prop-1-ynyl]-1,4-dihydro-2H-1l.-
sup.6-benzo[1,2,4]thiadiazin-3-one;
4-{1,1,3-Trioxo-7-[3-(3-methoxyphenyl)-
-prop-1-ynyl]-4-methyl-3,4-dihydro-1H-1l.sup.6-benzo[1,2,4]thiadiazin-2-yl-
methyl}-benzoic acid; and
4-{1,1,3-Trioxo-7-[3-(3-methoxyphenyl)-prop-1-yn-
yl]-3,4-dihydro-1H-1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl}-benzoic
acid.
12. A compound of Formula V 97or a pharmaceutically acceptable salt
thereof, or a tautomer thereof, wherein: G.sub.1 and G.sub.2
independently are 98wherein E is independently O or S; A is
OR.sub.1 or NR.sub.1R.sub.2; R.sub.1 and R.sub.2 independently are
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, (CH.sub.2).sub.naryl,
(CH.sub.2).sub.ncycloalkyl, or (CH.sub.2).sub.nheteroaryl, or
R.sub.1 and R.sub.2 are taken together with the nitrogen atom to
which they are attached to complete a 3- to 8-membered ring having
carbon atoms, the nitrogen atom bearing R.sub.1 and R.sub.2, and 0
or 1 heteroatom selected from N(H), N(CH.sub.3), O, and S, and
which ring is optionally unsubstituted or substituted with .dbd.O,
halo, or methyl, wherein n is an integer of from 0 to 6; or G.sub.1
and G.sub.2 independently are hydrogen, halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
(CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4; m is an integer of from 0
to 6; q is an integer of 0 or 1; R.sub.3 and R.sub.4 independently
are hydrogen, C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; Y is O or S; R.sub.5, R.sub.6,
and R.sub.7 independently are hydrogen, halo, hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, NO.sub.2, CN, CF.sub.3, or
NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10 independently are
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken together with
the nitrogen atom to which they are attached to complete a 3- to
7-membered ring having carbon atoms, the nitrogen atom bearing
R.sub.9 and R.sub.10, and 0 or 1 heteroatoms selected from N(H),
N(CH.sub.3), O, and S; R.sub.8 is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 alkanoyl, CH.sub.2CO.sub.2H, NH.sub.2, or
OH; and -- is a bond or is absent.
13. The compound according to claim 12, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, wherein: Y is O;
G.sub.1 and G.sub.2 independently are (CH.sub.2).sub.maryl, wherein
m is I and aryl is phenyl, (CH.sub.2).sub.msubstituted aryl,
wherein m is 1 and substituted aryl is 4-methoxyphenyl,
3-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-chlorophenyl,
3-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-nitrophenyl,
3-nitrophenyl, 4-methylsulfanylphenyl, 3-methylsulfanylphenyl,
4-methylphenyl, 3-methylphenyl, 4-cyanophenyl, 3-cyanophenyl,
4-carboxyphenyl, 3-carboxyphenyl, 4-methanesulfonylphenyl,
3-methanesulfonylphenyl, 4-methoxycarbonyphenyl, or
3-methoxycarbonylphenyl, (CH.sub.2).sub.mheteroaryl, wherein m is 1
and heteroaryl is pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl, or
(CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl; R.sub.5, R.sub.6,
and R.sub.7 are hydrogen; and R.sub.8 is methyl.
14. The compound according to claim 12, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, selected from:
1-Methyl-6-(4-methoxy-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1H-quinoli-
n-4-one;
3-(4-Methanesulfonyl-benzyl)-1-methyl-6-(4-methoxy-phenyl)-prop-1-
-ynyl)-1H-quinolin-4-one;
1-Methyl-6-(3-methoxy-phenyl)-prop-1-ynyl)-3-(4--
carboxybenzyl)-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-1-methyl-6--
(3-methoxy-phenyl)-prop-1-ynyl)-1H-quinolin-4-one;
6-(4-Cyano-phenyl)-prop-
-1-ynyl)-1-methyl-3-(4-carboxybenzyl)-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(4-cyano-phenyl)-prop-1-ynyl)-1-methyl-1H--
quinolin-4-one;
6-(3-Cyano-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-meth-
yl-1H-quinolin-4-one;
4-(4-Methanesulfonyl-benzyl)-6-(3-cyano-phenyl)-prop-
-1-ynyl)-1-methyl-1H-quinolin-4-one;
6-(4-Fluoro-phenyl)-prop-1-ynyl)-3-(4-
-carboxybenzyl)-1-methyl-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-
-(4-fluoro-phenyl)-prop-1-ynyl)-1-methyl-1H-quinolin-4-one;
6-(3-Fluoro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-quinolin-
-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(3-fluoro-phenyl)-prop-1-ynyl)-1-me-
thyl-1H-quinolin-4-one;
6-(4-Chloro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzy-
l)-1-methyl-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(4-chloro-ph-
enyl)-prop-1-ynyl)-1-methyl-1H-quinolin-4-one;
6-(3-Chloro-phenyl)-prop-1--
ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(3-chloro-phenyl)-prop-1-ynyl)-1-methyl-1H-
-quinolin-4-one;
6-(4-Bromo-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-met-
hyl-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(4-bromo-phenyl)-pro-
p-1-ynyl)-1-methyl-1H-quinolin-4-one;
6-(3-Bromo-phenyl)-prop-1-ynyl)-3-(4-
-carboxybenzyl)-1-methyl-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-
-(3-bromo-phenyl)-prop-1-ynyl)-1-methyl-1H-quinolin-4-one;
6-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-
-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(4-methanesulfanyl-phenyl)-
-prop-1-ynyl)-1-methyl-1H-quinolin-4-one;
6-(3-Methanesulfanyl-phenyl)-pro-
p-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(3-methanesulfanyl-phenyl)-prop-1-ynyl)-1--
methyl-1H-quinolin-4-one;
6-(4-Methyl-phenyl)-prop-1-ynyl)-3-(4-carboxyben-
zyl)-1-methyl-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(4-methyl--
phenyl)-prop-1-ynyl)-1-methyl-1H-quinolin-4-one;
6-(3-Methyl-phenyl)-prop--
1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(3-methyl-phenyl)-prop-1-ynyl)-1-methyl-1H-
-quinolin-4-one;
6-(3-Pyridin-4-yl-prop-1-ynyl)-3-(4-carboxybenzyl)-1-meth-
yl-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-4-yl-prop--
1-ynyl)-1-methyl-1H-quinolin-4-one;
6-(3-Pyridin-3-yl-prop-1-ynyl)-3-(4-ca- rboxybenzyl)-1-methyl
-1H-quinolin-4-one; 3-(4-Methanesulfonyl-benzyl)-6-(-
3-pyridin-3-yl-prop-1-ynyl)-1-methyl-1H-quinolin-4-one;
6-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-3-(4-carboxybenzyl)-1-methyl-1-
H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-[3-(2-methoxy-pyridin-4-y-
l)-prop-1-ynyl]-1-methyl-1H-quinolin-4-one;
1-Methyl-6-(4-methoxy-phenyl)--
prop-1-ynyl)-3-(4-carboxybenzyl)-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-1-methyl-6-(4-methoxy-phenyl)-prop-1-ynyl)-2-
,3-dihydro-1H-quinolin-4-one;
1-Methyl-6-(3-methoxy-phenyl)-prop-1-ynyl)-3-
-(4-carboxybenzyl)-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-ben-
zyl)-1-methyl-6-(3-methoxy-phenyl)-prop-1-ynyl)-2,3-dihydro-1H-quinolin-4--
one;
6-(4-Cyano-phenyl)-prop-1-ynyl)-1-methyl-3-(4-carboxybenzyl)-2,3-dihy-
dro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(4-cyano-phenyl)-pro-
p-1-ynyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
6-(3-Cyano-phenyl)-prop--
1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
4-(4-Methanesulfonyl-benzyl)-6-(3-cyano-phenyl)-prop-1-ynyl)-1-methyl-2,3-
-dihydro-1H-quinolin-4-one;
6-(4-Fluoro-phenyl)-prop-1-ynyl)-3-(4-carboxyb-
enzyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl-
)-6-(4-fluoro-phenyl)-prop-1-ynyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
6-(3-Fluoro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-dihydro-
-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(3-fluoro-phenyl)-prop--
1-ynyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
6-(4-Chloro-phenyl)-prop-1-
-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(4-chloro-phenyl)-prop-1-ynyl)-1-methyl-2,-
3-dihydro-1H-quinolin-4-one;
6-(3-Chloro-phenyl)-prop-1-ynyl)-3-(4-carboxy-
benzyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzy-
l)-6-(3-chloro-phenyl)-prop-1-ynyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one-
;
6-(4-Bromo-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-dihydro-
-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(4-bromo-phenyl)-prop-1-
-ynyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
6-(3-Bromo-phenyl)-prop-1-y- nyl)-3-(4-carboxybenzyl)-1-methyl
-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(3-bromo-phenyl)-prop-1-ynyl)-1-methyl-2,3-
-dihydro-1H-quinolin-4-one;
6-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-3-(4-
-carboxybenzyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(4-methanesulfanyl-phenyl)-prop-1-ynyl)-1--
methyl-2,3-dihydro-1H-quinolin-4-one;
6-(3-Methanesulfanyl-phenyl)-prop-1--
ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(3-methanesulfanyl-phenyl)-prop-1-ynyl)-1--
methyl-2,3-dihydro-1H-quinolin-4-one;
6-(4-Methyl-phenyl)-prop-1-ynyl)-3-(- 4-carboxybenzyl)-1-methyl
-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(4-methyl-phenyl)-prop-1-ynyl)-1-methyl-2,-
3-dihydro-1H-quinolin-4-one;
6-(3-Methyl-phenyl)-prop-1-ynyl)-3-(4-carboxy-
benzyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzy-
l)-6-(3-methyl-phenyl)-prop-1-ynyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one-
;
6-(3-Pyridin-4-yl-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-dihydro--
1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-4-yl-prop-1-y-
nyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
6-(3-Pyridin-3-yl-prop-1-ynyl-
)-3-(4-carboxybenzyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-3-yl-prop-1-ynyl)-1-methyl-2,3--
dihydro-1H-quinolin-4-one;
6-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-3-(4-
-carboxybenzyl)-1-methyl-2,3-dihydro-1H-quinolin-4-one; and
3-(4-Methanesulfonyl-benzyl)-6-[3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl]-1-
-methyl-2,3-dihydro-1H-quinolin-4-one.
15. A compound of Formula VI 99or a pharmaceutically acceptable
salt thereof, or a tautomer thereof, wherein: G.sub.1 and G.sub.2
independently are 100wherein E is independently O or S; A is
OR.sub.1 or NR.sub.1R.sub.2; R.sub.1 and R.sub.2 independently are
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, (CH.sub.2).sub.naryl,
(CH.sub.2).sub.ncycloalkyl, or (CH.sub.2).sub.nheteroaryl, or
R.sub.1 and R.sub.2 are taken together with the nitrogen atom to
which they are attached to complete a 3- to 8-membered ring having
carbon atoms, the nitrogen atom bearing R.sub.1 and R.sub.2, and 0
or 1 heteroatom selected from N(H), N(CH.sub.3), O, and S, and
which ring is optionally unsubstituted or substituted with .dbd.O,
halo, or methyl, wherein n is an integer of from 0 to 6; or G.sub.1
and G.sub.2 independently are hydrogen, halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
(CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4; m is an integer of from 0
to 6; q is an integer of 0 or 1; R.sub.3 and R.sub.4 independently
are hydrogen, C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; Y is O or S: R.sub.5, R.sub.6,
and R.sub.7 independently are hydrogen, halo, hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, NO.sub.2, CN, CF.sub.3, or
NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10 independently are
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken together with
the nitrogen atom to which they are attached to complete a 3- to
7-membered ring having carbon atoms, the nitrogen atom bearing
R.sub.9 and R.sub.10, and 0 or 1 heteroatoms selected from N(H),
N(CH.sub.3), O, and S; and X is S, (SO), S(O).sub.2, O, N(R.sub.8),
wherein R.sub.8 is as defined above, C(O), or CH.sub.2.
16. The compound according to claim 15, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, wherein Y ix O; X
is S; G.sub.1 and G.sub.2 independently are (CH.sub.2).sub.maryl,
wherein m is 1 and aryl is phenyl, (CH.sub.2).sub.msubstituted
aryl, wherein m is 1 and substituted aryl is 4-methoxyphenyl,
3-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-chlorophenyl,
3-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 3,4-difluorophenyl,
3-fluoro-4-methoxyphenyl, 4-nitrophenyl, 3-nitrophenyl,
4-methylsulfanylphenyl, 3-methylsulfanylphenyl, 4-methylphenyl,
3-methylphenyl, 4-cyanophenyl, 3-cyanophenyl, 4-carboxyphenyl,
3-carboxyphenyl, 4-methanesulfonylphenyl, 3-methanesulfonylphenyl,
4-methoxycarbonyphenyl, or 3-methoxycarbonylphenyl,
(CH.sub.2).sub.mheteroaryl, wherein m is 1 and heteroaryl is
pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl, or
(CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl; and R.sub.5,
R.sub.6, and R.sub.7 are hydrogen.
17. The compound according to claim 15, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, selected from:
2-(Phenyl)-prop-1-ynyl)-6-benzyl-4H-thiazolo[3,2-a]pyridin-5-one;
2-(4-Methoxy-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2-a]p-
yridin-5-one;
6-(4-Methanesulfonyl-benzyl)-2-(4-methoxy-phenyl)-prop-1-yny-
l)-4H-thiazolo[3,2-a]pyridin-5-one;
2-(3-Methoxy-phenyl)-prop-1-ynyl)-6-(4-
-carboxybenzyl)-4H-thiazolo[3,2-a]pyridin-5-one;
6-(4-Methanesulfonyl-benz-
yl)-2-(3-methoxy-phenyl)-prop-1-ynyl)-4H-thiazolo[3,2-a]pyridin-5-one;
2-(4-Cyano-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2-a]pyr-
idin-5-one;
6-(4-Methanesulfonyl-benzyl)-2-(4-cyano-phenyl)-prop-1-ynyl)-4-
H-thiazolo[3,2-a]pyridin-5-one;
2-(3-Cyano-phenyl)-prop-1-ynyl)-6-(4-carbo-
xybenzyl)-4H-thiazolo[3,2-a]pyridin-5-one;
6-(4-Methanesulfonyl-benzyl)-2--
(3-cyano-phenyl)-prop-1-ynyl)-4H-thiazolo[3,2-a]pyridin-5-one;
2-(4-Fluoro-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2-a]py-
ridin-5-one;
6-(4-Methanesulfonyl-benzyl)-2-(4-fluoro-phenyl)-prop-1-ynyl)-
-4H-thiazolo[3,2-a]pyridin-5-one;
2-(3-Fluoro-phenyl)-prop-1-ynyl)-6-(4-ca-
rboxybenzyl)-4H-thiazolo[3,2-a]pyridin-5-one;
6-(4-Methanesulfonyl-benzyl)-
-2-(3-fluoro-phenyl)-prop-1-ynyl)-4H-thiazolo[3,2-a]pyridin-5-one;
2-(4-Chloro-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)4H-thiazolo[3,2-a]pyr-
idin-5-one;
6-(4-Methanesulfonyl-benzyl)-2-(4-chloro-phenyl)-prop-1-ynyl)--
4H-thiazolo[3,2-a]pyridin-5-one;
2-(3-Chloro-phenyl)-prop-1-ynyl)-6-(4-car-
boxybenzyl)-4H-thiazolo[3,2-a]pyridin-5-one;
6-(4-Methanesulfonyl-benzyl)--
2-(3-chloro-phenyl)-prop-1-ynyl)-4H-thiazolo[3,2-a]pyridin-5-one;
2-(4-Bromo-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2-a]pyr-
idin-5-one;
6-(4-Methanesulfonyl-benzyl)-2-(4-bromo-phenyl)-prop-1-ynyl)-4-
H-thiazolo[3,2-a]pyridin-5-one;
2-(3-Bromo-phenyl)-prop-1-ynyl)-6-(4-carbo-
xybenzyl)-4H-thiazolo[3,2-a]pyridin-5-one;
6-(4-Methanesulfonyl-benzyl)-2--
(3-bromo-phenyl)-prop-1-ynyl)-4H-thiazolo[3,2-a]pyridin-5-one;
2-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo-
[3,2-a]pyridin-5-one;
6-(4-Methanesulfonyl-benzyl)-2-(4-methanesulfanyl-ph-
enyl)-prop-1-ynyl)-4H-thiazolo[3,2-a]pyridin-5-one;
2-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo-
[3,2-a]pyridin-5-one;
6-(4-Methanesulfonyl-benzyl)-2-(3-methanesulfanyl-ph-
enyl)-prop-1-ynyl)-4H-thiazolo[3,2-a]pyridin-5-one;
2-(4-Methyl-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2-a]py-
ridin-5-one;
6-(4-Methanesulfonyl-benzyl)-2-(4-methyl-phenyl)-prop-1-ynyl)-
-4H-thiazolo[3,2-a]pyridin-5-one;
2-(3-Methyl-phenyl)-prop-1-ynyl)-6-(4-ca-
rboxybenzyl)-4H-thiazolo[3,2-a]pyridin-5-one;
6-(4-Methanesulfonyl-benzyl)-
-2-(3-methyl-phenyl)-prop-1-ynyl)-4H-thiazolo[3,2-a]pyridin-5-one;
2-(3-Pyridin-4-yl-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2-a]pyri-
din-5-one;
6-(4-Methanesulfonyl-benzyl)-2-(3-pyridin-4-yl-prop-1-ynyl)-4H--
thiazolo[3,2-a]pyridin-5-one;
2-(3-Pyridin-3-yl-prop-1-ynyl)-6-(4-carboxyb-
enzyl)-4H-thiazolo[3,2-a]pyridin-S-one;
6-(4-Methanesulfonyl-benzyl)-2-(3--
pyridin-3-yl-prop-1-ynyl)-4H-thiazolo[3,2-a]pyridin-S-one;
2-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-6-(4-carboxybenzyl)-4H-thiazol-
o[3,2-a]pyridin-5-one; and
6-(4-Methanesulfonyl-benzyl)-2-[3-(2-methoxy-py-
ridin-4-yl)-prop-1-ynyl]-4H-thiazolo[3,2-a]pyridin-5-one.
18. A compound of Formula VII 101or a pharmaceutically acceptable
salt thereof, or a tautomer thereof, wherein: G.sub.1 and G.sub.2
independently are 102wherein E is independently O or S; A is
OR.sub.1 or NR.sub.1R.sub.2; R.sub.1 and R.sub.2 independently are
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, (CH.sub.2).sub.naryl,
(CH.sub.2).sub.ncycloalkyl, or (CH.sub.2).sub.nheteroaryl, or
R.sub.1 and R.sub.2 are taken together with the nitrogen atom to
which they are attached to complete a 3- to 8-membered ring having
carbon atoms, the nitrogen atom bearing R.sub.1 and R.sub.2, and 0
or 1 heteroatom selected from N(H), N(CH.sub.3), O, and S, and
which ring is optionally unsubstituted or substituted with .dbd.O,
halo, or methyl, wherein n is an integer of from 0 to 6; or G.sub.1
and G.sub.2 independently are hydrogen, halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
(CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4; m is an integer of from 0
to 6; q is an integer of 0 or 1; R.sub.3 and R.sub.4 independently
are hydrogen, C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; Y is O or S: R.sub.5, R.sub.6,
and R.sub.7 independently are hydrogen, halo, hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, NO.sub.2, CN, CF.sub.3, or
NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10 independently are
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken together with
the nitrogen atom to which they are attached to complete a 3- to
7-membered ring having carbon atoms, the nitrogen atom bearing
R.sub.9 and R.sub.10, and 0 or 1 heteroatoms selected from N(H),
N(CH.sub.3), O, and S; and X is S, (SO), S(O).sub.2, O, N(R.sub.8),
wherein R.sub.8 is as defined above, C(O), or CH.sub.2.
19. The compound according to claim 18, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, wherein Y ix O; X
is S; G.sub.1 and G.sub.2 independently are (CH.sub.2).sub.maryl,
wherein m is 1 and aryl is phenyl, (CH.sub.2).sub.msubstituted
aryl, wherein m is 1 and substituted aryl is 4-methoxyphenyl,
3-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-chlorophenyl,
3-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 3,4-difluorophenyl,
3-fluoro-4-methoxyphenyl, 4-nitrophenyl, 3-nitrophenyl,
4-methylsulfanylphenyl, 3-methylsulfanylphenyl, 4-methylphenyl,
3-methylphenyl, 4-cyanophenyl, 3-cyanophenyl, 4-carboxyphenyl,
3-carboxyphenyl, 4-methanesulfonylphenyl, 3-methanesulfonylphenyl,
4-methoxycarbonyphenyl, or 3-methoxycarbonylphenyl,
(CH.sub.2).sub.mheteroaryl, wherein m is 1 and heteroaryl is
pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl, or
(CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl; and R.sub.5,
R.sub.6, and R.sub.7 are hydrogen.
20. The compound according to claim 18, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, selected from:
2-(Phenyl-prop-1-ynyl)-5-(4-benzyl)-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Methoxy-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c]pyr-
idin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-methoxy-phenyl)-prop-1-ynyl)-
-5H-thieno[3,2-c]pyridin-4-one;
2-(3-Methoxy-phenyl)-prop-1-ynyl)-5-(4-car-
boxybenzyl)-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2--
(3-methoxy-phenyl)-prop-1-ynyl)-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Cyano-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c]pyrid-
in-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-cyano-phenyl)-prop-1-ynyl)-5H--
thieno[3,2-c]pyridin-4-one;
2-(3-Cyano-phenyl)-prop-1-ynyl)-5-(4-carboxybe-
nzyl)-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-cya-
no-phenyl)-prop-1-ynyl)-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Fluoro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c]pyri-
din-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-fluoro-phenyl)-prop-1-ynyl)-5-
H-thieno[3,2-c]pyridin-4-one;
2-(3-Fluoro-phenyl)-prop-1-ynyl)-5-(4-carbox-
ybenzyl)-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3--
fluoro-phenyl)-prop-1-ynyl)-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Chloro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)5H-thieno[3,2-c]pyrid-
in-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-chloro-phenyl)-prop-1-ynyl)-5H-
-thieno[3,2-c]pytidin-4-one;
2-(3-Chloro-phenyl)-prop-1-ynyl)-5-(4-carboxy-
benzyl)-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-c-
hloro-phenyl)-prop-1-ynyl)-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Bromo-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c]pyrid-
in-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-bromo-phenyl)-prop-1-ynyl)-5H--
thieno[3,2-c]pyridin-4-one;
2-(3-Bromo-phenyl)-prop-1-ynyl)-5-(4-carboxybe-
nzyl)-5H-thieno[3,2-c]pyridin-4-one;.
5-(4-Methanesulfonyl-benzyl)-2-(3-br-
omo-phenyl)-prop-1-ynyl)-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3-
,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-methanesulfanyl-phen-
yl)-prop-1-ynyl)-5H-thieno[3,2-c]pyridin-4-one;
2-(3-Methanesulfanyl-pheny-
l)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-methanesulfanyl-phenyl)-prop-1-ynyl)-5H-
-thieno[3,2-c]pyridin-4-one;
2-(4-Methyl-phenyl)-prop-1-ynyl)-5-(4-carboxy-
benzyl)-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-m-
ethyl-phenyl)-prop-1-ynyl)-5H-thieno[3,2-c]pyridin-4-one;
2-(3-Methyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c]pyri-
din-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-methyl-phenyl)-prop-1-ynyl)-5-
H-thieno[3,2-c]pyridin-4-one;
2-(3-Pyridin-4-yl-prop-1-ynyl)-5-(4-carboxyb-
enzyl)-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-py-
ridin-4-yl-prop-1-ynyl)-5H-thieno[3,2-c]pyridin-4-one;
2-(3-Pyridin-3-yl-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c]pyridi-
n-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-pyridin-3-yl-prop-1-ynyl)-5H-th-
ieno[3,2-c]pyridin-4-one;
2-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-5-(4--
carboxybenzyl)-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-
-2-[3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl]-5H-thieno[3,2-c]pyridin-4-one;
2-(Phenyl-prop-1-ynyl)-5-(4-benzyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-on-
e;
2-(4-Methoxy-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thien-
o[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-methoxy-phenyl)-p-
rop-1-ynyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
2-(3-Methoxy-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thieno[-
3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-methoxy-phenyl)-pro-
p-1-ynyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Cyano-phenyl)-prop--
1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-cyano-phenyl)-prop-1-ynyl)-7-methyl-5H--
thieno[3,2-c]pyridin-4-one;
2-(3-Cyano-phenyl)-prop-1-ynyl)-5-(4-carboxybe-
nzyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-
-2-(3-cyano-phenyl)-prop-1-ynyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Fluoro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thieno[3-
,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-fluoro-phenyl)-prop--
1-ynyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
2-(3-Fluoro-phenyl)-prop-1-
-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-fluoro-phenyl)-prop-1-ynyl)-7-methyl-5H-
-thieno[3,2-c]pyridin-4-one;
2-(4-Chloro-phenyl)-prop-1-ynyl)-5-(4-carboxy-
benzyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzy-
l)-2-(4-chloro-phenyl)-prop-1-ynyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one-
;
2-(3-Chloro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thieno[-
3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-chloro-phenyl)-prop-
-1-ynyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Bromo-phenyl)-prop-1-
-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-bromo-phenyl)-prop-1-ynyl)-7-methyl-5H--
thieno[3,2-c]pyridin-4-one;
2-(3-Bromo-phenyl)-prop-1-ynyl)-5-(4-carboxybe-
nzyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-
-2-(3-bromo-phenyl)-prop-1-ynyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-7-methyl-5-(4-carboxybenzyl)-5H-
-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-methanesulf-
anyl-phenyl)-prop-1-ynyl)-7-methyl -5H-thieno[3,2-c]pyridin-4-one;
2-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-
-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-methanesulf-
anyl-phenyl)-prop-1-ynyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
2-(4-Methyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thieno[3-
,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(4-methyl-phenyl)-prop--
1-ynyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
2-(3-Methyl-phenyl)-prop-1-
-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-methyl-phenyl)-prop-1-ynyl)-7-methyl-5H-
-thieno[3,2-c]pyridin-4-one;
2-(3-Pyridin-4-yl-prop-1-ynyl)-5-(4-carboxybe-
nzyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-
-2-(3-pyridin-4-yl-prop-1-ynyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
2-(3-Pyridin-3-yl-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thieno[3,2-
-c]pyridin-4-one;
5-(4-Methanesulfonyl-benzyl)-2-(3-pyridin-3-yl-prop-1-yn-
yl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
2-[3-(2-Methoxy-pyridin-4-yl)--
prop-1-ynyl]-5-(4-carboxybenzyl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
and
5-(4-Methanesulfonyl-benzyl)-2-[3-(2-methoxy-pyridin-4-yl)-prop-1-yny-
l]-7-methyl-5H-thieno[3,2-c]pyridin-4-one.
21. A pharmaceutical composition, comprising a compound of claim 1,
or a pharmaceutically acceptable salt thereof, or a tautomer
thereof, together with a pharmaceutically acceptable carrier,
diluent, or excipient.
22. A pharmaceutical composition, comprising a compound of any one
of claims 3, 6, 9, 12, 15, and 18, or a pharmaceutically acceptable
salt thereof, or a tautomer thereof, together with a
pharmaceutically acceptable carrier, diluent, or excipient.
23. A method for inhibiting an MMP-13 enzyme in an animal,
comprising administering to the animal an MMP-13 inhibiting amount
of a compound of claim 1, or a pharmaceutically acceptable salt
thereof, or a tautomer thereof.
24. A method for treating cancer, comprising administering to a
patient having cancer and in need of treatment an anticancer
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof.
25. A method for treating arthritis, comprising administering to a
patient in need of treatment an anti-arthritic amount of a compound
of claim 1, or a pharmaceutically acceptable salt thereof, or a
tautomer thereof.
26. The method of claim 25, wherein the arthritis is
osteoarthritis.
27. The method of claim 25, wherein the arthritis is rheumatoid
arthritis.
28. The compound according to claim 1, selected from:
N-(4-Cyano-benzyl)-3-(3-[1,2,3]-triazol-1-yl-prop-1-ynyl)-benzamide;
N-(4-Cyano-benzyl)-3-(3-[1,2,3]-triazol-1-yl-prop-1-ynyl)-benzamide;
4-({3-[3-(4-Chloro-phenyl)-prop-1-ynyl]-benzoylamino}-methyl)-benzoic
acid;
4-({3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-benzoylamino}-methyl)-benzo-
ic acid; 3-Phenylethynyl-N-(4-Sulfamoyl-benzyl)-benzamide;
N-(4-Cyano-benzyl)-3-phenylethynyl-benzamide:
3-Phenylethylethynyl-N-pyri- din-4-yl-methyl-benzamide; and
3-[[3-(3-Phenylethylethynyl-benzoylamino]-m- ethyl}-benzoic acid;
or a pharmaceutically acceptable salt thereof.
29. The compound according to claim 1, selected from:
4-({[5-(3-Phenyl-prop-1-ynyl)-pyridine-3-carbonyl]-amino}-methyl)-benzoic
acid; and
4-{[(Phenylethynyl-pyridine-2-carbonyl)-amino]-methyl}-benzoic
acid; or a pharmaceutically acceptable salt thereof.
30. The compound according to claim 1, selected from:
4-[1-Methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2.lambda..s-
up.4-benzo[1,2,6]thiadiazin-3-yl methyl]benzoic acid;
4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-ynyl)-1,4-dihydro-2H-2.lambda.-
.sup.6-benzo[1,2,6]-thiadiazin-3-ylmethyl]benzoic acid;
4-[1,1,3-Trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1.lambda..sup.6-b-
enzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
2-(4-Methoxy-benzyl)-1,1-d-
ioxo-7-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-1.lambda..sup.6-benzo[1,2,4]t-
hiadiazin-3-one; and
4-[1,1,3-Trioxo-7-(4-phenyl-but-1-ynyl)-3,4-dihydro-1-
H-1.lambda..sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
or a pharmaceutically acceptable salt thereof.
31. A method for treating atherosclerosis, comprising administering
to a patient in need of treatment a therapeutically effective
amount of a compound of claim 1, or a pharmaceutically acceptable
salt thereof, or a tautomer thereof.
32. A method for treating age-related macular degeneration,
comprising administering to a patient in need of treatment a
therapeutically effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt thereof, or a tautomer
thereof.
33. A method for treating osteoporosis, comprising administering to
a patient in need of treatment a therapeutically effective amount
of a compound of claim 1, or a pharmaceutically acceptable salt
thereof, or a tautomer thereof.
34. A method for treating multiple sclerosis, comprising
administering to a patient in need of treatment a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof.
35. A method for treating inflammatory bowel disease, comprising
administering to a patient in need of treatment a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof.
36. A method for treating psoriasis, comprising administering to a
patient in need of treatment a therapeutically effective amount of
a compound of claim 1, or a pharmaceutically acceptable salt
thereof, or a tautomer thereof.
37. A method for treating a periodontal disease, comprising
administering to a patient in need of treatment a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof.
38. A method for treating chronic obstructive pulmonary disease,
comprising administering to a patient in need of treatment a
therapeutically effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt thereof, or a tautomer
thereof.
39. A method for treating arthritis other than osteoarthritis and
rheumatoid arthritis, comprising administering to a patient in need
of treatment a therapeutically effective amount of a compound of
claim 1, or a pharmaceutically acceptable salt thereof, or a
tautomer thereof.
40. A method for treating asthma, comprising administering to a
patient in need of treatment a therapeutically effective amount of
a compound of claim 1, or a pharmaceutically acceptable salt
thereof, or a tautomer thereof.
41. A method for treating cardiac insufficiency, comprising
administering to a patient in need of treatment a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims benefit of priority from PCT
International patent application no. PCT/IB02/03057, filed Aug. 2,
2002, and U.S. provisional patent application Nos. 60/395,254,
filed Jul. 12, 2002, and 60/329,216, filed Oct. 12, 2001.
FIELD OF THE INVENTION
[0002] This invention relates to a group of alkyne derivatives that
inhibit matrix metalloproteinase enzymes and are thus useful for
treating diseases resulting from tissue breakdown, such as heart
disease, multiple sclerosis, arthritis, including osteoarthritis
and rheumatoid arthritis, atherosclerosis, age-related macular
degeneration, chronic obstructive pulmonary disease, psoriasis,
asthma, cardiac insufficiency, inflammatory bowel disease,
periodontal diseases, and osteoporosis.
BACKGROUND OF THE INVENTION
[0003] Matrix metalloproteinases (sometimes referred to as MMPs)
are naturally-occurring enzymes found in most mammals.
Over-expression and activation of MMPs or an imbalance between MMPs
and inhibitors of MMPs have been suggested as factors in the
pathogenesis of diseases characterized by the breakdown of
extracellular matrix or connective tissues.
[0004] Stromelysin-1 and gelatinase A are members of the matrix
metalloproteinases (MMP) family. Other members include fibroblast
collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B
(92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3
(MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13), TNF-alpha
converting enzyme (TACE), and other newly discovered
membrane-associated matrix metalloproteinases (Sato H., Takino T.,
Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature,
1994;370:61-65). These enzymes have been implicated with a number
of diseases which result from breakdown of connective tissue,
including such diseases as rheumatoid arthritis, osteoarthritis,
osteoporosis, periodontitis, multiple sclerosis, gingivitis,
corneal epidermal and gastric ulceration, atherosclerosis,
neointimal proliferation which leads to restenosis and ischemic
heart failure, and tumor metastasis. A method for preventing and
treating these and other diseases is now recognized to be by
inhibiting metalloproteinase enzymes, thereby curtailing and/or
eliminating the breakdown of connective tissues that results in the
disease states.
[0005] The catalytic zinc in matrix metalloproteinases is typically
the focal point for inhibitor design. The modification of
substrates by introducing zinc-chelating groups has generated
potent inhibitors such as peptide hydroxamates and thiol-containing
peptides. Peptide hydroxamates and the natural endogenous
inhibitors of MMPs (TIMPs) have been used successfully to treat
animal models of cancer and inflammation. MMP inhibitors have also
been used to prevent and treat congestive heart failure and other
cardiovascular diseases, U.S. Pat. No. 5,948,780.
[0006] A major limitation on the use of currently known MMP
inhibitors is their lack of specificity for any particular enzyme.
Recent data has established that specific MMP enzymes are
associated with some diseases, with no effect on others. The MMPs
are generally categorized based on their substrate specificity, and
indeed the collagenase subfamily of MMP-1, MMP-8, and MMP-13
selectively cleave native interstitial collagens, and thus are
associated only with diseases linked to such interstitial collagen
tissue. This is evidenced by the recent discovery that MMP-13 alone
is over expressed in breast carcinoma, while MMP-1 alone is over
expressed in papillary carcinoma (see Chen et al., J. Am. Chem.
Soc., 2000;122:9648-9654).
[0007] There appears to be few selective inhibitors of MMP-13
reported. A compound named WAY-170523 has been reported by Chen et
al., supra., 2000, and a few other compounds are reported in PCT
International Publication No. WO 01/63244 A1, as allegedly
selective inhibitors of MMP-13. Further, U.S. Pat. No. 6,008,243
discloses inhibitors of MMP-13. However, no selective or
nonselective inhibitor of MMP-13 has been approved and marketed for
the treatment of any disease in any mammal. Accordingly, the need
continues to find new low molecular weight compounds that are
potent and selective MMP inhibitors, and that have an acceptable
therapeutic index of toxicity/potency to make them amenable for use
clinically in the prevention and treatment of the associated
disease states. An object of this invention is to provide a group
of selective MMP-13 inhibitor compounds characterized as being
alkynes.
SUMMARY OF THE INVENTION
[0008] This invention provides a group of alkyne compounds that are
inhibitors of matrix metalloproteinase enzymes, and especially
MMP-13. The invention is more particularly directed to compounds
defined by Formula I 2
[0009] or a pharmaceutically acceptable salt thereof, or a tautomer
thereof, wherein:
[0010] G.sub.1 and G.sub.2 independently are 3
[0011] wherein
[0012] E is independently O or S;
[0013] A is OR.sub.1 or NR.sub.1R.sub.2;
[0014] R.sub.1 and R.sub.2 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.naryl, (CH.sub.2).sub.ncycloalkyl, or
(CH.sub.2).sub.nheteroaryl, or R.sub.1 and R.sub.2 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 8-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.1 and R.sub.2, and 0 or 1 heteroatom selected
from N(H), N(CH.sub.3), O, and S, and which ring is optionally
unsubstituted or substituted with =O, halo, or methyl, wherein
[0015] n is an integer of from 0 to 6; or
[0016] G.sub.1 and G.sub.2 independently are hydrogen, halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4;
[0017] m is an integer of from 0 to 6;
[0018] q is an integer of 0 or 1;
[0019] R.sub.3 and R.sub.4 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S;
[0020] B is: 45
[0021] wherein:
[0022] each Y is independently O or S;
[0023] R.sub.5, R.sub.6, and R.sub.7 independently are hydrogen,
halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, NO.sub.2,
NR.sub.9R.sub.10, CN, or CF.sub.3, wherein R.sub.9 and R.sub.10
independently are hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken
together with the nitrogen atom to which they are attached to form
a 3- to 7-membered ring having carbon atoms, the nitrogen atom
bearing R.sub.9 and R.sub.10, and 0 or 1 atoms selected from O, S,
N(H), and N(CH.sub.3);
[0024] R.sub.8 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, CH.sub.2CO.sub.2H, OH, NH.sub.2,
or C.sub.1-C.sub.6 alkanoyl;
[0025] X is S, S(O), S(O).sub.2, O, N(R.sub.8), wherein R.sub.8 is
as defined above, C(.dbd.O), or CH.sub.2; and
[0026] -- is a bond or is absent.
[0027] Preferred is a compound of Formula I, or a pharmaceutically
acceptable salt thereof, or tautomer thereof, wherein
[0028] G.sub.1 and G.sub.2 independently are
[0029] (CH.sub.2).sub.maryl,
[0030] (CH.sub.2).sub.msubstituted aryl,
[0031] (CH.sub.2).sub.mheteroaryl, or
[0032] (CH.sub.2).sub.msubstituted heteroaryl, wherein m is an
integer of from 0 to 6 and aryl, substituted aryl, heteroaryl, and
substituted heteroaryl are as defined above for Formula I.
[0033] Another embodiment of the invention is a compound according
to Formula I of Formula II 6
[0034] or a pharmaceutically acceptable salt thereof, or a tautomer
thereof,
[0035] wherein:
[0036] G.sub.1 and G.sub.2 independently are 7
[0037] wherein
[0038] E is independently O or S;
[0039] A is OR.sub.1 or NR.sub.1R.sub.2;
[0040] R.sub.1 and R.sub.2 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.naryl, (CH.sub.2).sub.ncycloalkyl, or
(CH.sub.2).sub.nheteroaryl, or R.sub.1 and R.sub.2 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 8-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.1 and R.sub.2, and 0 or 1 heteroatom selected
from N(H), N(CH.sub.3), O, and S, and which ring is optionally
unsubstituted or substituted with .dbd.O, halo, or methyl,
wherein
[0041] n is an integer of from 0 to 6; or
[0042] G.sub.1 and G.sub.2 independently are hydrogen, halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4;
[0043] m is an integer of from 0 to 6;
[0044] q is an integer of 0 or 1;
[0045] R.sub.3 and R.sub.4 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; and
[0046] R.sub.5, R.sub.6, and R.sub.7 independently are hydrogen,
halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, NO.sub.2, CN,
CF.sub.3, or NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10
independently are hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.9 and R.sub.10, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S.
[0047] Preferred is a compound of Formula II, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, wherein:
[0048] G.sub.1and G.sub.2 independently are
[0049] (CH.sub.2).sub.maryl, wherein m is 1 and aryl is phenyl,
[0050] (CH.sub.2).sub.msubstituted aryl, wherein m is 1 and
substituted aryl is
[0051] 4-methoxyphenyl, 3-methoxyphenyl, 4-fluorophenyl,
[0052] 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl,
4-bromophenyl,
[0053] 3-bromophenyl, 4-nitrophenyl, 3-nitrophenyl,
[0054] 4-methylsulfanylphenyl, 3-methylsulfanylphenyl,
4-methylphenyl,
[0055] 3-methylphenyl, 4-cyanophenyl, 3-cyanophenyl,
4-carboxyphenyl,
[0056] 3-carboxyphenyl, 4-methanesulfonylphenyl, or
[0057] 3-methanesulfonylphenyl,
[0058] (CH.sub.2).sub.mheteroaryl, wherein m is 1 and heteroaryl is
pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl, or
[0059] (CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl; and
[0060] R.sub.5, R.sub.6, and R.sub.8 are hydrogen.
[0061] More preferred is a compound of Formula II, or a
pharmaceutically acceptable salt thereof, or a tautomer thereof,
selected from:
[0062]
3-(4-Methoxy-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0063]
N-(4-Methanesulfonyl-benzyl)-3-(4-methoxy-phenyl)-prop-1-ynyl)-benz-
amide;
[0064]
3-(3-Methoxy-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0065]
N-(4-Methanesulfonyl-benzyl)-3-(3-methoxy-phenyl)-prop-1-ynyl)-benz-
amide;
[0066]
3-(4-Cyano-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0067]
N-(4-Methanesulfonyl-benzyl)-3-(4-cyano-phenyl)-prop-1-ynyl)-benzam-
ide;
[0068]
3-(3-Cyano-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0069]
N-(4-Methanesulfonyl-benzyl)-3-(3-cyano-phenyl)-prop-1-ynyl)-benzam-
ide;
[0070]
3-(4-Fluoro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0071]
N-(4-Methanesulfonyl-benzyl)-3-(4-fluoro-phenyl)-prop-1-ynyl)-benza-
mide;
[0072]
3-(3-Fluoro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0073]
N-(4-Methanesulfonyl-benzyl)-3-(3-fluoro-phenyl)-prop-1-ynyl)-benza-
mide;
[0074]
3-(4-Chloro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0075]
N-(4-Methanesulfonyl-benzyl)-3-(4-chloro-phenyl)-prop-1-ynyl)-benza-
mide;
[0076]
3-(3-Chloro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0077]
N-(4-Methanesulfonyl-benzyl)-3-(3-chloro-phenyl)-prop-1-ynyl)-benza-
mide;
[0078]
3-(.sup.4-Bromo-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0079]
N-(4-Methanesulfonyl-benzyl)-3-(4-bromo-phenyl)-prop-1-ynyl)-benzam-
ide;
[0080]
3-(3-Bromo-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0081]
N-(4-Methanesulfonyl-benzyl)-3-(3-bromo-phenyl)-prop-1-ynyl)-benzam-
ide;
[0082]
3-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benza-
mide;
[0083]
N-(4-Methanesulfonyl-benzyl)-3-(4-methanesulfanyl-phenyl)-prop-1-yn-
yl)-benzamide;
[0084]
3-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benza-
mide;
[0085]
N-(4-Methanesulfonyl-benzyl)-3-(3-methanesulfanyl-phenyl)-prop-1-yn-
yl)-benzamide;
[0086]
3-(4-Methyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0087] N-(4-Methanesulfonyl-benzyl)-3-
(4-methyl-phenyl)-prop-1-ynyl)-benz- amide;
[0088]
3-(3-Methyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0089]
N-(4-Methanesulfonyl-benzyl)-3-(3-methyl-phenyl)-prop-1-ynyl)-benza-
mide;
[0090]
3-(3-Pyridin-4-yl-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0091]
N-(4-Methanesulfonyl-benzyl)-3-(3-pyridin-4-yl-prop-1-ynyl)-benzami-
de;
[0092]
3-(3-Pyridin-3-yl-prop-1-ynyl)-N-(4-carboxybenzyl)-benzamide;
[0093]
N-(4-Methanesulfonyl-benzyl)-3-(3-pyridin-3-yl-prop-1-ynyl)-benzami-
de;
[0094]
3-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-N-(4-carboxybenzyl)-benz-
amide; and
[0095]
N-(4-Methanesulfonyl-benzyl)-3-[3-(2-methoxy-pyridin-4-yl)-prop-1-y-
nyl]-benzamide.
[0096] Another embodiment of the invention is a compound according
to Formula I of Formula III 8
[0097] or a pharmaceutically acceptable salt thereof, or a tautomer
thereof, wherein:
[0098] G.sub.1 and G.sub.2 independently are 9
[0099] wherein
[0100] E is independently O or S;
[0101] A is OR.sub.1 or NR.sub.1R.sub.2;
[0102] R.sub.1 and R.sub.2 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.naryl, (CH.sub.2).sub.ncycloalkyl, or
(CH.sub.2).sub.nheteroaryl, or R.sub.1 and R.sub.2 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 8-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.1 and R.sub.2, and 0 or 1 heteroatom selected
from N(H), N(CH.sub.3), O, and S, and which ring is optionally
unsubstituted or substituted with .dbd.O, halo, or methyl,
wherein
[0103] n is an integer of from 0 to 6; or
[0104] G.sub.1 and G.sub.2 independently are hydrogen, halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4;
[0105] m is an integer of from 0 to 6;
[0106] q is an integer of 0 or 1;
[0107] R.sub.3 and R.sub.4 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; and
[0108] R.sub.5 and R.sub.6 independently are hydrogen, halo,
hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, NO.sub.2, CN,
CF.sub.3, or NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10
independently are hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.9 and R.sub.10, and 0 or 1 atoms selected from
N(H), N(CH.sub.3), O, and S.
[0109] Preferred is a compound of Formula III, or a
pharmaceutically acceptable salt thereof, or a tautomer thereof,
wherein:
[0110] G.sub.1 and G.sub.2 independently are
[0111] (CH.sub.2).sub.maryl, wherein m is 1 and aryl is phenyl,
[0112] (CH.sub.2).sub.msubstituted aryl, wherein m is 1 and
substituted aryl is
[0113] 4-methoxyphenyl, 3-methoxy phenyl, 4-fluorophenyl,
[0114] 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl,
4-bromophenyl,
[0115] 3-bromophenyl, 4-nitrophenyl, 3-nitrophenyl,
[0116] 4-methylsulfanylphenyl, 3-methylsulfanylphenyl,
4-methylphenyl,
[0117] 3-methylphenyl, 4-cyanophenyl, 3-cyanophenyl,
4-carboxyphenyl,
[0118] 3-carboxyphenyl, 4-methanesulfonylphenyl, or
[0119] 3-methanesulfonylphenyl,
[0120] (CH.sub.2).sub.mheteroaryl, wherein m is 1 and heteroaryl is
pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl, or
[0121] (CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl; and
[0122] R.sub.5 and R.sub.6 are hydrogen.
[0123] More preferred is a compound of Formula III, or a
pharmaceutically acceptable salt thereof, or a tautomer thereof,
selected from:
[0124]
3-(4-Methoxy-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinami-
de;
[0125]
N-(4-Methanesulfonyl-benzyl)-3-(4-methoxy-phenyl)-prop-1-ynyl)-ison-
icotinamide;
[0126]
3-(3-Methoxy-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinami-
de;
[0127]
N-(4-Methanesulfonyl-benzyl)-3-(3-methoxy-phenyl)-prop-1-ynyl)-ison-
icotinamide;
[0128]
3-(4-Cyano-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamide-
;
[0129]
N-(4-Methanesulfonyl-benzyl)-3-(4-cyano-phenyl)-prop-1-ynyl)-isonic-
otinamide;
[0130]
3-(3-Cyano-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamide-
;
[0131]
N-(4-Methanesulfonyl-benzyl)-3-(3-cyano-phenyl)-prop-1-ynyl)-isonic-
otinamide;
[0132]
3-(4-Fluoro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamid-
e;
[0133]
N-(4-Methanesulfonyl-benzyl)-3-(4-fluoro-phenyl)-prop-1-ynyl)-isoni-
cotinamide;
[0134]
3-(3-Fluoro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamid-
e;
[0135]
N-(4-Methanesulfonyl-benzyl)-3-(3-fluoro-phenyl)-prop-1-ynyl)-isoni-
cotinamide;
[0136]
3-(4-Chloro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamid-
e;
[0137]
N-(4-Methanesulfonyl-benzyl)-3-(4-chloro-phenyl)-prop-1-ynyl)-isoni-
cotinamide;
[0138]
3-(3-Chloro-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamid-
e;
[0139]
N-(4-Methanesulfonyl-benzyl)-3-(3-chloro-phenyl)-prop-1-ynyl)-isoni-
cotinamide;
[0140]
3-(4-Bromo-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamide-
;
[0141]
N-(4-Methanesulfonyl-benzyl)-3-(4-bromo-phenyl)-prop-1-ynyl)-isonic-
otinamide;
[0142]
3-(3-Bromo-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamide-
;
[0143]
N-(4-Methanesulfonyl-benzyl)-3-(3-bromo-phenyl)-prop-1-ynyl)-isonic-
otinamide;
[0144]
3-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isoni-
cotinamide;
[0145]
N-(4-Methanesulfonyl-benzyl)-3-(4-methanesulfanyl-phenyl)-prop-1-yn-
yl)-isonicotinamide;
[0146]
3-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isoni-
cotinamide;
[0147]
N-(4-Methanesulfonyl-benzyl)-3-(3-methanesulfanyl-phenyl)-prop-1-yn-
yl)-isonicotinamide;
[0148]
3-(4-Methyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamid-
e;
[0149]
N-(4-Methanesulfonyl-benzyl)-3-(4-methyl-phenyl)-prop-1-ynyl)-isoni-
cotinamide;
[0150]
3-(3-Methyl-phenyl)-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamid-
e;
[0151]
N-(4-Methanesulfonyl-benzyl)-3-(3-methyl-phenyl)-prop-1-ynyl)-isoni-
cotinamide;
[0152]
3-(3-pyridin-4-yl-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamide;
[0153]
N-(4-Methanesulfonyl-benzyl)-3-(3-pyridin-4-yl-prop-1-ynyl)-isonico-
tinamide;
[0154]
3-(3-Pyridin-3-yl-prop-1-ynyl)-N-(4-carboxybenzyl)-isonicotinamide;
[0155]
N-(4-Methanesulfonyl-benzyl)-3-(3-pyridin-3-yl-prop-1-ynyl)-isonico-
tinamide;
[0156]
3-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl)-N-(4-carboxybenzyl)-ison-
icotinamide; and
[0157]
N-(4-Methanesulfonyl-benzyl)-3-[3-(2-methoxy-pyridin-4-yl)-prop-1-y-
nyl]-isonicotinamide.
[0158] Another embodiment of the invention is a compound according
to Formula I of Formula IV 10
[0159] or a pharmaceutically acceptable salt thereof, or a tautomer
thereof,
[0160] wherein:
[0161] G.sub.1 and G.sub.2 independently are 11
[0162] wherein
[0163] E is independently O or S;
[0164] A is OR.sub.1 or NR.sub.1R.sub.2;
[0165] R.sub.1 and R.sub.2 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.naryl, (CH.sub.2).sub.ncycloalkyl, or
(CH.sub.2).sub.nheteroaryl, or R.sub.1 and R.sub.2 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 8-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.1 and R.sub.2, and 0 or 1 heteroatom selected
from N(H), N(CH.sub.3), O, and S, and which ring is optionally
unsubstituted or substituted with .dbd.O, halo, or methyl, wherein
n is an integer of from 0 to 6; or
[0166] G.sub.1 and G.sub.2 independently are hydrogen, halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4;
[0167] m is an integer of from 0 to 6;
[0168] q is an integer of 0 or 1;
[0169] R.sub.3 and R.sub.4 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S;
[0170] Y is independently O or S;
[0171] R.sub.5, R.sub.6, and R.sub.7 independently are hydrogen,
halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, NO.sub.2, CN,
CF.sub.3, or NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10
independently are hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.9 and R.sub.10, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; and
[0172] R.sub.8 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkanoyl, CH.sub.2CO.sub.2H, NH.sub.2, or OH.
[0173] Preferred is a compound of Formula IV, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, wherein:
[0174] Y is O;
[0175] G.sub.1 and G.sub.2 independently are
[0176] (CH.sub.2).sub.maryl, wherein m is 1 and aryl is phenyl,
[0177] (CH.sub.2).sub.msubstituted aryl, wherein m is 1 and
substituted aryl is
[0178] 4-methoxyphenyl, 3-methoxyphenyl, 4-fluorophenyl,
[0179] 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl,
4-bromophenyl,
[0180] 3-bromophenyl, 4-nitrophenyl, 3-nitrophenyl,
[0181] 4-methylsulfanylphenyl, 3-methylsulfanylphenyl,
4-methylphenyl,
[0182] 3-methylphenyl, 4-cyanophenyl, 3-cyanophenyl,
4-carboxyphenyl,
[0183] 3-carboxyphenyl, 4-methanesulfonylphenyl, or
[0184] 3-methanesulfonylphenyl,
[0185] (CH.sub.2).sub.mheteroaryl, wherein m is 1 and heteroaryl is
piperidin-1-yl, piperazin-1-yl, tetrahydrofuran-2-yl, pyridin-4-yl,
pyridin-3-yl, or pyridin-2-yl,
[0186] (CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl, or
[0187] (CH.sub.2).sub.mcycloalkyl, wherein m is 1 and cycloalkyl is
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;
and
[0188] R.sub.8 is hydrogen or methyl.
[0189] More preferred is a compound of Formula IV, a
pharmaceutically acceptable salt thereof, or a tautomer thereof,
selected from:
[0190]
2-Benzyl-4-methyl-1,1-dioxo-7-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-
-1l.sup.6-benzo[1,2,4]thiadiazin-3-one;
[0191]
4-[4-Methyl-1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1l-
.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
[0192]
2-Benzyl-1,1-dioxo-7-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-1l.sup.6-
-benzo[1,2,4]thiadiazin-3-one;
[0193]
4-[1,1,3-Trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1l.sup.6-be-
nzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
[0194]
2-Benzyl-4-methyl-1,1-dioxo-7-[3-(4-methoxyphenyl)-prop-1-ynyl]-1,4-
-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one;
[0195]
2-Benzyl-1,1-dioxo-7-[3-(4-methoxyphenyl)-prop-1-ynyl]-1,4-dihydro--
2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one;
[0196]
4-{1,1,3-Trioxo-7-[3-(4-methoxyphenyl)-prop-1-ynyl]-4-methyl-3,4-di-
hydro-1H-1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl}-benzoic
acid;
[0197]
4-{1,1,3-Trioxo-7-[3-(4-methoxyphenyl)-prop-1-ynyl]-3,4-dihydro-1H--
1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl}-benzoic acid;
[0198]
2-Benzyl-4-methyl-1,1-dioxo-7-[3-(3-methoxyphenyl)-prop-1-ynyl]-1,4-
-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one;
[0199]
2-Benzyl-1,1-dioxo-7-[3-(3-methoxyphenyl)-prop-1-ynyl]-1,4-dihydro--
2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one;
[0200]
4-{1,1,3-Trioxo-7-[3-(3-methoxyphenyl)-prop-1-ynyl]-4-methyl-3,4-di-
hydro-1H-1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl}-benzoic acid;
and
[0201]
4-{1,1,3-Trioxo-7-[3-(3-methoxyphenyl)-prop-1-ynyl]-3,4-dihydro-1H--
1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl}-benzoic acid.
[0202] Another embodiment of the invention is a compound according
to Formula I of Formula V 12
[0203] or a pharmaceutically acceptable salt thereof, or a tautomer
thereof, wherein:
[0204] G.sub.1 and G.sub.2 independently are 13
[0205] wherein
[0206] E is independently O or S;
[0207] A is OR.sub.1 or NR.sub.1R.sub.2;
[0208] R.sub.1 and R.sub.2 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.naryl, (CH.sub.2).sub.ncycloalkyl, or
(CH.sub.2).sub.nheteroaryl, or R.sub.1 and R.sub.2 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 8-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.1 and R.sub.2, and 0 or 1 heteroatom selected
from N(H), N(CH.sub.3), O, and S, and which ring is optionally
unsubstituted or substituted with .dbd.O, halo, or methyl, wherein
n is an integer of from 0 to 6; or
[0209] G.sub.1 and G.sub.2 independently are hydrogen, halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4;
[0210] m is an integer of from 0 to 6;
[0211] q is an integer of 0 or 1;
[0212] R.sub.3 and R.sub.4 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S;
[0213] Y is O or S;
[0214] R.sub.5, R.sub.6, and R.sub.7 independently are hydrogen,
halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, NO.sub.2, CN,
CF.sub.3, or NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10
independently are hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.9 and R.sub.10, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S;
[0215] R.sub.8 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkanoyl, CH.sub.2CO.sub.2H, NH.sub.2, or OH;
and
[0216] -- is a bond or is absent.
[0217] Preferred is a compound of Formula V, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, wherein:
[0218] Y is O;
[0219] G.sub.1 and G.sub.2 independently are
[0220] (CH.sub.2).sub.maryl, wherein m is 1 and aryl is phenyl,
[0221] (CH.sub.2).sub.msubstituted aryl, wherein m is 1 and
substituted aryl is
[0222] 4-methoxyphenyl, 3-methoxyphenyl, 4-fluorophenyl,
[0223] 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl,
4-bromophenyl,
[0224] 3-bromophenyl, 4-nitrophenyl, 3-nitrophenyl,
[0225] 4-methylsulfanylphenyl, 3-methylsulfanylphenyl,
4-methylphenyl,
[0226] 3-methylphenyl, 4-cyanophenyl, 3-cyanophenyl,
4-carboxyphenyl,
[0227] 3-carboxyphenyl, 4-methanesulfonylphenyl,
[0228] 3-methanesulfonylphenyl, 4-methoxycarbonyphenyl, or
[0229] 3-methoxycarbonylphenyl,
[0230] (CH.sub.2).sub.mheteroaryl, wherein m is 1 and heteroaryl is
pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl, or
[0231] (CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl;
[0232] R.sub.5, R.sub.6, and R.sub.7 are hydrogen; and
[0233] R.sub.8 is methyl.
[0234] More preferred is a compound of Formula V, or a
pharmaceutically acceptable salt thereof, or a tautomer thereof,
selected from:
[0235]
1-Methyl-6-(4-methoxy-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1H-q-
uinolin-4-one;
[0236]
3-(4-Methanesulfonyl-benzyl)-1-methyl-6-(4-methoxy-phenyl)-prop-1-y-
nyl)-1H-quinolin-4-one;
[0237]
1-Methyl-6-(3-methoxy-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1H-q-
uinolin-4-one;
[0238]
3-(4-Methanesulfonyl-benzyl)-1-methyl-6-(3-methoxy-phenyl)-prop-1-y-
nyl)-1H-quinolin-4-one;
[0239]
6-(4-Cyano-phenyl)-prop-1-ynyl)-1-methyl-3-(4-carboxybenzyl)-1H-qui-
nolin-4-one;
[0240]
3-(4-Methanesulfonyl-benzyl)-6-(4-cyano-phenyl)-prop-1-ynyl)-1-meth-
yl-1H-quinolin-4-one;
[0241]
6-(3-Cyano-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-qui-
nolin-4-one;
[0242]
4-(4-Methanesulfonyl-benzyl)-6-(3-cyano-phenyl)-prop-1-ynyl)-1-meth-
yl-1H-quinolin-4-one;
[0243]
6-(4-Fluoro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-qu-
inolin-4-one;
[0244]
3-(4-Methanesulfonyl-benzyl)-6-(4-fluoro-phenyl)-prop-1-ynyl)-1-met-
hyl-1H-quinolin-4-one;
[0245]
6-(3-Fluoro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-qu-
inolin-4-one;
[0246]
3-(4-Methanesulfonyl-benzyl)-6-(3-fluoro-phenyl)-prop-1-ynyl)-1-met-
hyl-1H-quinolin-4-one;
[0247]
6-(4-Chloro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-qu-
inolin-4-one;
[0248]
3-(4-Methanesulfonyl-benzyl)-6-(4-chloro-phenyl)-prop-1-ynyl)-1-met-
hyl-1H-quinolin-4-one;
[0249]
6-(3-Chloro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-qu-
inolin-4-one;
[0250]
3-(4-Methanesulfonyl-benzyl)-6-(3-chloro-phenyl)-prop-1-ynyl)-1-met-
hyl-1H-quinolin-4-one;
[0251]
6-(4-Bromo-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-qui-
nolin-4-one;
[0252]
3-(4-Methanesulfonyl-benzyl)-6-(4-bromo-phenyl)-prop-1-ynyl)-1-meth-
yl-1H-quinolin-4-one;
[0253]
6-(3-Bromo-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-qui-
nolin-4-one;
[0254]
3-(4-Methanesulfonyl-benzyl)-6-(3-bromo-phenyl)-prop-1-ynyl)-1-meth-
yl- 1H-quinolin-4-one;
[0255]
6-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-met-
hyl-1H-quinolin-4-one;
[0256]
3-(4-Methanesulfonyl-benzyl)-6-(4-methanesulfanyl-phenyl)-prop-1-yn-
yl)-1-methyl-1H-quinolin-4-one;
[0257]
6-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-met-
hyl-1H-quinolin-4-one;
[0258]
3-(4-Methanesulfonyl-benzyl)-6-(3-methanesulfanyl-phenyl)-prop-1-yn-
yl)-1-methyl-1H-quinolin-4-one;
[0259]
6-(4-Methyl-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-qu-
inolin-4-one;
[0260]
3-(4-Methanesulfonyl-benzyl)-6-(4-methyl-phenyl)-prop-1-ynyl)-1-met-
hyl-1H-quinolin-4-one;
[0261]
6-(3-Methyl-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-qu-
inolin-4-one;
[0262] 3-(4-Methanesulfonyl-benzyl)-6-(3-methyl-phenyl)-prop- I
-ynyl)-1-methyl-1H-quinolin-4-one;
[0263]
6-(3-Pyridin-4-yl-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-quin-
olin-4-one;
[0264]
3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-4-yl-prop-1-ynyl)-1-methy-
l-1H-quinolin-4-one;
[0265]
6-(3-Pyridin-3-yl-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-1H-quin-
olin-4-one;
[0266]
3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-3-yl-prop-1-ynyl)-1-methy-
l-1H-quinolin-4-one;
[0267]
6-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-3-(4-carboxybenzyl)-1-me-
thyl-1H-quinolin-4-one;
[0268]
3-(4-Methanesulfonyl-benzyl)-6-[3-(2-methoxy-pyridin-4-yl)-prop-1-y-
nyl]-1-methyl-1H-quinolin-4-one;
[0269]
1-Methyl-6-(4-methoxy-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-2,3--
dihydro-1H-quinolin-4-one;
[0270]
3-(4-Methanesulfonyl-benzyl)-1-methyl-6-(4-methoxy-phenyl)-prop-1-y-
nyl)-2,3-dihydro-1H-quinolin-4-one;
[0271]
1-Methyl-6-(3-methoxy-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-2,3--
dihydro-1H-quinolin-4-one;
[0272]
3-(4-Methanesulfonyl-benzyl)-1-methyl-6-(3-methoxy-phenyl)-prop-1-y-
nyl)-2,3-dihydro-1H-quinolin-4-one;
[0273]
6-(4-Cyano-phenyl)-prop-1-ynyl)-1-methyl-3-(4-carboxybenzyl)-2,3-di-
hydro-1H-quinolin-4-one;
[0274]
3-(4-Methanesulfonyl-benzyl)-6-(4-cyano-phenyl)-prop-1-ynyl)-1-meth-
yl-2,3-dihydro-1H-quinolin-4-one;
[0275]
6-(3-Cyano-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-di-
hydro-1H-quinolin-4-one;
[0276]
4-(4-Methanesulfonyl-benzyl)-6-(3-cyano-phenyl)-prop-1-ynyl)-1-meth-
yl-2,3-dihydro-1H-quinolin-4-one;
[0277]
6-(4-Fluoro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-d-
ihydro-1H-quinolin-4-one;
[0278]
3-(4-Methanesulfonyl-benzyl)-6-(4-fluoro-phenyl)-prop-1-ynyl)-1-met-
hyl-2,3-dihydro-1H-quinolin-4-one;
[0279]
6-(3-Fluoro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-d-
ihydro-1H-quinolin-4-one;
[0280]
3-(4-Methanesulfonyl-benzyl)-6-(3-fluoro-phenyl)-prop-1-ynyl)-1-met-
hyl-2,3-dihydro-1H-quinolin-4-one;
[0281]
6-(4-Chloro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-d-
ihydro-1H-quinolin-4-one;
[0282]
3-(4-Methanesulfonyl-benzyl)-6-(4-chloro-phenyl)-prop-1-ynyl)-1-met-
hyl-2,3-dihydro-1H-quinolin-4-one;
[0283]
6-(3-Chloro-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-d-
ihydro-1H-quinolin-4-one;
[0284]
3-(4-Methanesulfonyl-benzyl)-6-(3-chloro-phenyl)-prop-1-ynyl)-1-met-
hyl-2,3-dihydro-1H-quinolin-4-one;
[0285]
6-(4-Bromo-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-di-
hydro-1H-quinolin-4-one;
[0286]
3-(4-Methanesulfonyl-benzyl)-6-(4-bromo-phenyl)-prop-1-ynyl)-1-meth-
yl-2,3-dihydro-1H-quinolin-4-one;
[0287]
6-(3-Bromo-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-di-
hydro-1H-quinolin-4-one;
[0288]
3-(4-Methanesulfonyl-benzyl)-6-(3-bromo-phenyl)-prop-1-ynyl)-1-meth-
yl-2,3-dihydro-1H-quinolin-4-one;
[0289]
6-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-met-
hyl-2,3-dihydro-1H-quinolin-4-one;
[0290]
3-(4-Methanesulfonyl-benzyl)-6-(4-methanesulfanyl-phenyl)-prop-1-yn-
yl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
[0291]
6-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-met-
hyl-2,3-dihydro-1H-quinolin-4-one;
[0292]
3-(4-Methanesulfonyl-benzyl)-6-(3-methanesulfanyl-phenyl)-prop-1-yn-
yl)-1-methyl-2,3-dihydro-1H-quinolin-4-one;
[0293]
6-(4-Methyl-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-d-
ihydro-1H-quinolin-4-one;
[0294]
3-(4-Methanesulfonyl-benzyl)-6-(4-methyl-phenyl)-prop-1-ynyl)-1-met-
hyl-2,3-dihydro-1H-quinolin-4-one;
[0295]
6-(3-Methyl-phenyl)-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-d-
ihydro-1H-quinolin-4-one;
[0296]
3-(4-Methanesulfonyl-benzyl)-6-(3-methyl-phenyl)-prop-1-ynyl)-1-met-
hyl-2,3-dihydro-1H-quinolin-4-one;
[0297]
6-(3-pyridin-4-yl-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-dih-
ydro-1H-quinolin-4-one;
[0298]
3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-4-yl-prop-1-ynyl)-1-methy-
l-2,3-dihydro-1H-quinolin-4-one;
[0299]
6-(3-Pyridin-3-yl-prop-1-ynyl)-3-(4-carboxybenzyl)-1-methyl-2,3-dih-
ydro-1H-quinolin-4-one;
[0300]
3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-3-yl-prop-1-ynyl)-1-methy-
l-2,3-dihydro-1H-quinolin-4-one;
[0301]
6-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-3-(4-carboxybenzyl)-1-me-
thyl-2,3-dihydro-1H-quinolin-4-one; and
[0302]
3-(4-Methanesulfonyl-benzyl)-6-[3-(2-methoxy-pyridin-4-yl)-prop-1-y-
nyl]-1-methyl-2,3-dihydro-1H-quinolin-4-one.
[0303] Another embodiment of the invention is a compound according
to Formula I of Formula VI 14
[0304] or a pharmaceutically acceptable salt thereof, or a tautomer
thereof, wherein:
[0305] G.sub.1 and G.sub.2 independently are 15
[0306] wherein
[0307] E is independently O or S;
[0308] A is OR.sub.1 or NR.sub.1R.sub.2;
[0309] R.sub.1 and R.sub.2 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.naryl, (CH.sub.2).sub.ncycloalkyl, or
(CH.sub.2).sub.nheteroaryl, or R.sub.1 and R.sub.2 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 8-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.1 and R.sub.2, and 0 or 1 heteroatom selected
from N(H), N(CH.sub.3), O, and S, and which ring is optionally
unsubstituted or substituted with .dbd.O, halo, or methyl, wherein
n is an integer of from 0 to 6; or
[0310] G.sub.1 and G.sub.2 independently are hydrogen, halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(C.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.sub- .3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4;
[0311] m is an integer of from 0 to 6;
[0312] q is an integer of 0 or 1;
[0313] R.sub.3 and R.sub.4 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S;
[0314] Y is O or S:
[0315] R.sub.5, R.sub.6, and R.sub.7 independently are hydrogen,
halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, NO.sub.2, CN,
CF.sub.3, or NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10
independently are hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.9 and R.sub.10, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; and
[0316] X is S, (SO), S(O).sub.2, O, N(R.sub.8), wherein R.sub.8 is
as defined above, C(O), or CH.sub.2.
[0317] Preferred is a compound of Formula VI, or a pharmaceutically
acceptable salt thereof, or a tautomer thereof, wherein:
[0318] Y ix O;
[0319] X is S;
[0320] G.sub.1 and G.sub.2 independently are
[0321] (CH.sub.2).sub.maryl, wherein m is 1 and aryl is phenyl,
[0322] (CH.sub.2).sub.msubstituted aryl, wherein m is 1 and
substituted aryl is
[0323] 4-methoxyphenyl, 3-methoxyphenyl, 4-fluorophenyl,
[0324] 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl,
4-bromophenyl,
[0325] 3-bromophenyl, 3,4-difluorophenyl,
3-fluoro-4-methoxyphenyl,
[0326] 4-nitrophenyl, 3-nitrophenyl, 4-methylsulfanylphenyl,
[0327] 3-methylsulfanylphenyl, 4-methylphenyl, 3-methylphenyl,
[0328] 4-cyanophenyl, 3-cyanophenyl, 4-carboxyphenyl,
[0329] 3-carboxyphenyl, 4-methanesulfonylphenyl,
[0330] 3-methanesulfonylphenyl, 4-methoxycarbonyphenyl, or
[0331] 3-methoxycarbonylphenyl,
[0332] (CH.sub.2).sub.mheteroaryl, wherein m is 1 and heteroaryl is
pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl, or
[0333] (CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl; and
[0334] R.sub.5, R.sub.6, and R.sub.7 are hydrogen.
[0335] More preferred is a compound of Formula VI, or a
pharmaceutically acceptable salt thereof, or a tautomer thereof,
selected from:
[0336]
2-(Phenyl)-prop-1-ynyl)-6-benzyl-4H-thiazolo[3,2-a]pyridin-5-one;
[0337]
2-(4-Methoxy-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3-
,2-a]pyridin-5-one;
[0338]
6-(4-Methanesulfonyl-benzyl)-2-(4-methoxy-phenyl)-prop-1-ynyl)-4H-t-
hiazolo[3,2-a]pyridin-5-one;
[0339]
2-(3-Methoxy-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3-
,2-a]pyridin-S-one;
[0340]
6-(4-Methanesulfonyl-benzyl)-2-(3-methoxy-phenyl)-prop-1-ynyl)-4H-t-
hiazolo[3,2-a]pyridin-5-one;
[0341]
2-(4-Cyano-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2-
-a]pyridin-5-one;
[0342]
6-(4-Methanesulfonyl-benzyl)-2-(4-cyano-phenyl)-prop-1-ynyl)-4H-thi-
azolo[3,2-a]pyridin-5-one;
[0343]
2-(3-Cyano-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2-
-a]pyridin-5-one;
[0344]
6-(4-Methanesulfonyl-benzyl)-2-(3-cyano-phenyl)-prop-1-ynyl)-4H-thi-
azolo[3,2-a]pyridin-5-one;
[0345]
2-(4-Fluoro-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,-
2-a]pyridin-5-one;
[0346]
6-(4-Methanesulfonyl-benzyl)-2-(4-fluoro-phenyl)-prop-1-ynyl)-4H-th-
iazolo[3,2-a]pyridin-5-one;
[0347]
2-(3-Fluoro-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,-
2-a]pyridin-5-one;
[0348]
6-(4-Methanesulfonyl-benzyl)-2-(3-fluoro-phenyl)-prop-1-ynyl)-4H-th-
iazolo[3,2-a]pyridin-5-one;
[0349]
2-(4-Chloro-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)4H-thiazolo[3,2-
-a]pyridin-5-one;
[0350]
6-(4-Methanesulfonyl-benzyl)-2-(4-chloro-phenyl)-prop-1-ynyl)-4H-th-
iazolo[3,2-a]pyridin-5-one;
[0351]
2-(3-Chloro-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,-
2-a]pyridin-5-one;
[0352]
6-(4-Methanesulfonyl-benzyl)-2-(3-chloro-phenyl)-prop-1-ynyl)-4H-th-
iazolo[3,2-a]pyridin-5-one;
[0353]
2-(4-Bromo-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2-
-a]pyridin-5-one;
[0354]
6-(4-Methanesulfonyl-benzyl)-2-(4-bromo-phenyl)-prop-1-ynyl)-4H-thi-
azolo[3,2-a]pyridin-5-one;
[0355]
2-(3-Bromo-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2-
-a]pyridin-5-one;
[0356]
6-(4-Methanesulfonyl-benzyl)-2-(3-bromo-phenyl)-prop-1-ynyl)-4H-thi-
azolo[3,2-a]pyridin-5-one;
[0357]
2-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-th-
iazolo[3,2-a]pyridin-5-one;
[0358]
6-(4-Methanesulfonyl-benzyl)-2-(4-methanesulfanyl-phenyl)-prop-1-yn-
yl)-4H-thiazolo[3,2-a]pyridin-5-one;
[0359]
2-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-th-
iazolo[3,2-a]pyridin-5-one;
[0360]
6-(4-Methanesulfonyl-benzyl)-2-(3-methanesulfanyl-phenyl)-prop-1-yn-
yl)-4H-thiazolo[3,2-a]pyridin-5-one;
[0361]
2-(4-Methyl-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,-
2-a]pyridin-5-one;
[0362]
6-(4-Methanesulfonyl-benzyl)-2-(4-methyl-phenyl)-prop-1-ynyl)-4H-th-
iazolo[3,2-a]pyridin-S-one;
[0363]
2-(3-Methyl-phenyl)-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,-
2-a]pyridin-5-one;
[0364]
6-(4-Methanesulfonyl-benzyl)-2-(3-methyl-phenyl)-prop-1-ynyl)-4H-th-
iazolo[3,2-a]pyridin-5-one;
[0365]
2-(3-Pyridin-4-yl-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2--
a]pyridin-5-one;
[0366]
6-(4-Methanesulfonyl-benzyl)-2-(3-pyridin-4-yl-prop-1-ynyl)-4H-thia-
zolo[3,2-a]pyridin-5-one;
[0367]
2-(3-Pyridin-3-yl-prop-1-ynyl)-6-(4-carboxybenzyl)-4H-thiazolo[3,2--
a]pyridin-5-one;
[0368]
6-(4-Methanesulfonyl-benzyl)-2-(3-pyridin-3-yl-prop-1-ynyl)-4H-thia-
zolo[3,2-a]pyridin-5-one;
[0369]
2-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-6-(4-carboxybenzyl)-4H-t-
hiazolo[3,2-a]pyridin-5-one; and
[0370]
6-(4-Methanesulfonyl-benzyl)-2-[3-(2-methoxy-pyridin-4-yl)-prop-1-y-
nyl]-4H-thiazolo[3,2-a]pyridin-5-one.
[0371] Another embodiment of the invention is a compound according
to claim 1 of Formula VII 16
[0372] or a pharmaceutically acceptable salt thereof, or a tautomer
thereof,
[0373] wherein:
[0374] G.sub.1 and G.sub.2 independently are 17
[0375] wherein
[0376] E is independently O or S;
[0377] A is OR.sub.1 or NR.sub.1R.sub.2;
[0378] R.sub.1 and R.sub.2 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.naryl, (CH.sub.2).sub.ncycloalkyl, or
(CH.sub.2).sub.nheteroaryl, or R.sub.1 and R.sub.2 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 8-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.1 and R.sub.2, and 0 or 1 heteroatom selected
from N(H), N(CH.sub.3), O, and S, and which ring is optionally
unsubstituted or substituted with .dbd.O, halo, or methyl, wherein
n is an integer of from 0 to 6; or
[0379] G.sub.1 and G.sub.2 independently are hydrogen, halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, (CH.sub.2).sub.mOH, (CH.sub.2).sub.mOR.sub.3,
(CH.sub.2).sub.mcycloalkyl, (CH.sub.2).sub.maryl,
(CH.sub.2).sub.msubstituted aryl, (CH.sub.2).sub.mheteroaryl,
(CH.sub.2).sub.msubstituted heteroaryl, CH(OH)(CH.sub.2).sub.maryl,
CHOH(CH.sub.2).sub.msubstituted aryl,
CH(OH)(CH.sub.2).sub.mheteroaryl, CH(OH)(CH.sub.2).sub.msubstituted
heteroaryl, (CO.sub.2)q(CH.sub.2).sub.maryl,
(CO.sub.2)q(CH.sub.2).sub.ms- ubstituted aryl,
(CO.sub.2)q(CH.sub.2).sub.mheteroaryl,
(CO.sub.2)q(CH.sub.2).sub.msubstituted heteroaryl,
(CO.sub.2)q(CH.sub.2).sub.mcarbocycle,
(CO.sub.2)q(CH.sub.2).sub.mheteroc- ycle,
(CO.sub.2)q(CH.sub.2).sub.mNR.sub.3R.sub.4,
(CH.sub.2).sub.mC(O)R.su- b.3, (CH.sub.2).sub.mC(O)OR.sub.3,
(CH.sub.2).sub.mC(O)NR.sub.3R.sub.4,
(CH.sub.2).sub.mC(S)NR.sub.3R.sub.4, or
(CH.sub.2).sub.mC(NH)NR.sub.3R.su- b.4;
[0380] m is an integer of from 0 to 6;
[0381] q is an integer of 0 or 1;
[0382] R.sub.3 and R.sub.4 independently are hydrogen,
C.sub.1-C.sub.6 alkyl, (CH.sub.2).sub.maryl, or
(CH.sub.2).sub.mheteroaryl, or R.sub.3 and R.sub.4 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.3 and R.sub.4, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S;
[0383] Y is O or S:
[0384] R.sub.5, R.sub.6, and R.sub.7 independently are hydrogen,
halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, NO.sub.2, CN,
CF.sub.3, or NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10
independently are hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, or benzyl, or R.sub.9 and R.sub.10 are taken
together with the nitrogen atom to which they are attached to
complete a 3- to 7-membered ring having carbon atoms, the nitrogen
atom bearing R.sub.9 and R.sub.10, and 0 or 1 heteroatoms selected
from N(H), N(CH.sub.3), O, and S; and
[0385] X is S, (SO), S(O).sub.2, O, N(R.sub.8), wherein R.sub.8 is
as defined above, C(O), or CH.sub.2.
[0386] Preferred is a compound of Formula VII, or a
pharmaceutically acceptable salt thereof, or a tautomer thereof,
wherein:
[0387] Y ix O;
[0388] X is S;
[0389] G.sub.1 and G.sub.2 independently are
[0390] (CH.sub.2).sub.maryl, wherein m is 1 and aryl is phenyl,
[0391] (CH.sub.2).sub.msubstituted aryl, wherein m is 1 and
substituted aryl is
[0392] 4-methoxyphenyl, 3-methoxyphenyl, 4-fluorophenyl,
[0393] 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl,
[0394] 4-bromophenyl, 3-bromophenyl, 3,4-difluorophenyl,
[0395] 3-fluoro-4-methoxyphenyl, 4-nitrophenyl, 3-nitrophenyl,
[0396] 4-methylsulfanylphenyl, 3-methylsulfanylphenyl,
[0397] 4-methylphenyl, 3-methylphenyl, 4-cyanophenyl,
[0398] 3-cyanophenyl, 4-carboxyphenyl, 3-carboxyphenyl,
[0399] 4-methanesulfonylphenyl, 3-methanesulfonylphenyl,
[0400] 4-methoxycarbonyphenyl, or 3-methoxycarbonylphenyl,
[0401] (CH.sub.2).sub.mheteroaryl, wherein m is 1 and heteroaryl is
pyridin-4-yl, pyridin-3-yl, or pyridin-2-yl, or
[0402] (CH.sub.2).sub.msubstituted heteroaryl, wherein m is 1 and
substituted heteroaryl is 2-methoxypyridin-4-yl; and
[0403] R.sub.5, R.sub.6, and R.sub.7 are hydrogen.
[0404] More preferred is a compound of Formula VII, or a
pharmaceutically acceptable salt thereof, or a tautomer thereof,
selected from:
[0405]
2-(Phenyl-prop-1-ynyl)-5-(4-benzyl)-5H-thieno[3,2-c]pyridin-4-one;
[0406]
2-(4-Methoxy-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-
-c]pyridin-4-one;
[0407]
5-(4-Methanesulfonyl-benzyl)-2-(4-methoxy-phenyl)-prop-1-ynyl)-5H-t-
hieno[3,2-c]pyridin-4-one;
[0408]
2-(3-Methoxy-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-
-c]pyridin-4-one;
[0409]
5-(4-Methanesulfonyl-benzyl)-2-(3-methoxy-phenyl)-prop-1-ynyl)-5H-t-
hieno[3,2-c]pyridin-4-one;
[0410]
2-(4-Cyano-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c-
]pyridin-4-one;
[0411]
5-(4-Methanesulfonyl-benzyl)-2-(4-cyano-phenyl)-prop-1-ynyl)-5H-thi-
eno[3,2-c]pyridin-4-one;
[0412]
2-(3-Cyano-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c-
]pyridin-4-one;
[0413]
5-(4-Methanesulfonyl-benzyl)-2-(3-cyano-phenyl)-prop-1-ynyl)-5H-thi-
eno[3,2-c]pyridin-4-one;
[0414]
2-(4-Fluoro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2--
c]pyridin-4-one;
[0415]
5-(4-Methanesulfonyl-benzyl)-2-(4-fluoro-phenyl)-prop-1-ynyl)-5H-th-
ieno[3,2-c]pyridin-4-one;
[0416]
2-(3-Fluoro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2--
c]pyridin-4-one;
[0417]
5-(4-Methanesulfonyl-benzyl)-2-(3-fluoro-phenyl)-prop-1-ynyl)-5H-th-
ieno[3,2-c]pyridin-4-one;
[0418]
2-(4-Chloro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)5H-thieno[3,2-c-
]pyridin-4-one;
[0419]
5-(4-Methanesulfonyl-benzyl)-2-(4-chloro-phenyl)-prop-1-ynyl)-5H-th-
ieno[3,2-c]pyridin-4-one;
[0420]
2-(3-Chloro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2--
c]pyridin-4-one;
[0421]
5-(4-Methanesulfonyl-benzyl)-2-(3-chloro-phenyl)-prop-1-ynyl)-5H-th-
ieno[3,2-c]pyridin-4-one;
[0422]
2-(4-Bromo-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c-
]pyridin-4-one;
[0423]
5-(4-Methanesulfonyl-benzyl)-2-(4-bromo-phenyl)-prop-1-ynyl)-5H-thi-
eno[3,2-c]pyridin-4-one;
[0424]
2-(3-Bromo-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c-
]pyridin-4-one;
[0425]
5-(4-Methanesulfonyl-benzyl)-2-(3-bromo-phenyl)-prop-1-ynyl)-5H-thi-
eno[3,2-c]pyridin-4-one;
[0426]
2-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-th-
ieno[3,2-c]pyridin-4-one;
[0427]
5-(4-Methanesulfonyl-benzyl)-2-(4-methanesulfanyl-phenyl)-prop-1-yn-
yl)-5H-thieno[3,2-c]pyridin-4-one;
[0428]
2-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-th-
ieno[3,2-c]pyridin-4-one;
[0429]
5-(4-Methanesulfonyl-benzyl)-2-(3-methanesulfanyl-phenyl)-prop-1-yn-
yl)-5H-thieno[3,2-c]pyridin-4-one;
[0430]
2-(4-Methyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2--
c]pyridin-4-one;
[0431]
5-(4-Methanesulfonyl-benzyl)-2-(4-methyl-phenyl)-prop-1-ynyl)-5H-th-
ieno[3,2-c]pyridin-4-one;
[0432]
2-(3-Methyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2--
c]pyridin-4-one;
[0433]
5-(4-Methanesulfonyl-benzyl)-2-(3-methyl-phenyl)-prop-1-ynyl)-5H-th-
ieno[3,2-c]pyridin-4-one;
[0434]
2-(3-Pyridin-4-yl-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c]-
pyridin-4-one;
[0435]
5-(4-Methanesulfonyl-benzyl)-2-(3-pyridin-4-yl-prop-1-ynyl)-5H-thie-
no[3,2-c]pyridin-4-one;
[0436]
2-(3-Pyridin-3-yl-prop-1-ynyl)-5-(4-carboxybenzyl)-5H-thieno[3,2-c]-
pyridin-4-one;
[0437]
5-(4-Methanesulfonyl-benzyl)-2-(3-pyridin-3-yl-prop-1-ynyl)-5H-thie-
no[3,2-c]pyridin-4-one;
[0438]
2-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-5-(4-carboxybenzyl)-5H-t-
hieno[3,2-c]pyridin-4-one;
[0439]
5-(4-Methanesulfonyl-benzyl)-2-[3-(2-methoxy-pyridin-4-yl)-prop-1-y-
nyl]-5H-thieno[3,2-c]pyridin-4-one;
[0440]
2-(Phenyl-prop-1-ynyl)-5-(4-benzyl)-7-methyl-5H-thieno[3,2-c]pyridi-
n-4-one;
[0441]
2-(4-Methoxy-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-t-
hieno[3,2-c]pyridin-4-one;
[0442]
5-(4-Methanesulfonyl-benzyl)-2-(4-methoxy-phenyl)-prop-1-ynyl)-7-me-
thyl-5H-thieno[3,2-c]pyridin-4-one;
[0443]
2-(3-Methoxy-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-t-
hieno[3,2-c]pyridin-4-one;
[0444]
5-(4-Methanesulfonyl-benzyl)-2-(3-methoxy-phenyl)-prop-1-ynyl)-7-me-
thyl-5H-thieno[3,2-c]pyridin-4-one;
[0445]
2-(4-Cyano-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thi-
eno[3,2-c]pyridin-4-one;
[0446]
5-(4-Methanesulfonyl-benzyl)-2-(4-cyano-phenyl)-prop-1-ynyl)-7-meth-
yl-5H-thieno[3,2-c]pyridin-4-one;
[0447]
2-(3-Cyano-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thi-
eno[3,2-c]pyridin-4-one;
[0448]
5-(4-Methanesulfonyl-benzyl)-2-(3-cyano-phenyl)-prop-1-ynyl)-7-meth-
yl-5H-thieno[3,2-c]pyridin-4-one;
[0449]
2-(4-Fluoro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-th-
ieno[3,2-c]pyridin-4-one;
[0450]
5-(4-Methanesulfonyl-benzyl)-2-(4-fluoro-phenyl)-prop-1-ynyl)-7-met-
hyl-5H-thieno[3,2-c]pyridin-4-one;
[0451]
2-(3-Fluoro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-th-
ieno[3,2-c]pyridin-4-one;
[0452]
5-(4-Methanesulfonyl-benzyl)-2-(3-fluoro-phenyl)-prop-1-ynyl)-7-met-
hyl-5H-thieno[3,2-c]pyridin-4-one;
[0453]
2-(4-Chloro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-th-
ieno[3,2-c]pyridin-4-one;
[0454]
5-(4-Methanesulfonyl-benzyl)-2-(4-chloro-phenyl)-prop-1-ynyl)-7-met-
hyl-5H-thieno[3,2-c]pyridin-4-one;
[0455]
2-(3-Chloro-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-th-
ieno[3,2-c]pyridin-4-one;
[0456]
5-(4-Methanesulfonyl-benzyl)-2-(3-chloro-phenyl)-prop-1-ynyl)-7-met-
hyl-5H-thieno[3,2-c]pyridin-4-one;
[0457]
2-(4-Bromo-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thi-
eno[3,2-c]pyridin-4-one;
[0458]
5-(4-Methanesulfonyl-benzyl)-2-(4-bromo-phenyl)-prop-1-ynyl)-7-meth-
yl-5H-thieno[3,2-c]pyridin-4-one;
[0459]
2-(3-Bromo-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thi-
eno[3,2-c]pyridin-4-one;
[0460]
5-(4-Methanesulfonyl-benzyl)-2-(3-bromo-phenyl)-prop-1-ynyl)-7-meth-
yl-5H-thieno[3,2-c]pyridin-4-one;
[0461]
2-(4-Methanesulfanyl-phenyl)-prop-1-ynyl)-7-methyl-5-(4-carboxybenz-
yl)-5H-thieno[3,2-c]pyridin-4-one;
[0462]
5-(4-Methanesulfonyl-benzyl)-2-(4-methanesulfanyl-phenyl)-prop-1-yn-
yl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
[0463]
2-(3-Methanesulfanyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-met-
hyl-5H-thieno[3,2-c]pyridin-4-one;
[0464]
5-(4-Methanesulfonyl-benzyl)-2-(3-methanesulfanyl-phenyl)-prop-1-yn-
yl)-7-methyl-5H-thieno[3,2-c]pyridin-4-one;
[0465]
2-(4-Methyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-th-
ieno[3,2-c]pyridin-4-one;
[0466]
5-(4-Methanesulfonyl-benzyl)-2-(4-methyl-phenyl)-prop-1-ynyl)-7-met-
hyl-5H-thieno[3,2-c]pyridin-4-one;
[0467]
2-(3-Methyl-phenyl)-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-th-
ieno[3,2-c]pyridin-4-one;
[0468]
5-(4-Methanesulfonyl-benzyl)-2-(3-methyl-phenyl)-prop-1-ynyl)-7-met-
hyl-5H-thieno[3,2-c]pyridin-4-one;
[0469]
2-(3-Pyridin-4-yl-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thie-
no[3,2-c]pyridin-4-one;
[0470]
5-(4-Methanesulfonyl-benzyl)-2-(3-pyridin-4-yl-prop-1-ynyl)-7-methy-
l-5H-thieno[3,2-c]pyridin-4-one;
[0471]
2-(3-Pyridin-3-yl-prop-1-ynyl)-5-(4-carboxybenzyl)-7-methyl-5H-thie-
no[3,2-c]pyridin-4-one;
[0472]
5-(4-Methanesulfonyl-benzyl)-2-(3-pyridin-3-yl-prop-1-ynyl)-7-methy-
l-5H-thieno[3,2-c]pyridin-4-one;
[0473]
2-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-5-(4-carboxybenzyl)-7-me-
thyl-5H-thieno[3,2-c]pyridin-4-one; and
[0474]
5-(4-Methanesulfonyl-benzyl)-2-[3-(2-methoxy-pyridin-4-yl)-prop-1-y-
nyl]-7-methyl-5H-thieno[3,2-c]pyridin-4-one.
[0475] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 18
[0476] wherein Y and R.sub.6 are as defined above for Formula
I.
[0477] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0478]
4-[2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2l.sup.4-benzo-
[d][1,2]thiazin-3-ylmethyl]-benzoic acid; and
[0479]
4-[2,2,4-trioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2l.sup.6-be-
nzo[d] [1,2]thiazin-3-ylmethyl]-benzoic acid.
[0480] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 19
[0481] wherein Y and R.sub.6 are as defined above for Formula
I.
[0482] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0483]
4-[1,3-dioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-3l.sup.4-thia--
2,6-diaza-naphthalen-2-ylmethyl]-benzoic acid; and
[0484]
4-[1,3,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-3l.sup.6-th-
ia-2,6-diaza-naphthalen-2-ylmethyl]-benzoic acid.
[0485] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 20
[0486] wherein Y is as defined above for Formula I.
[0487] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0488]
4-[2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-4H-2l.sup.4-benzo[e][1,2,3]ox-
athiazin-3-ylmethyl]-benzoic acid; and
[0489]
4-[2,2,4-trioxo-6-(3-phenyl-prop-1-ynyl)-4H-2l.sup.6-benzo[e][1,2,3-
]oxathiazin-3-ylmethyl]-benzoic acid.
[0490] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 21
[0491] wherein Y is as defined above for Formula I.
[0492] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0493]
4-[2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-4H-1-oxa-2l.sup.4-thia-3,7-di-
aza-naphthalen-3-ylmethyl]-benzoic acid; and
[0494]
4-[2,2,4-trioxo-6-(3-phenyl-prop-1-ynyl)-4H-1-oxa-2l.sup.6-thia-3,7-
-diaza-naphthalen-3-ylmethyl]-benzoic acid.
[0495] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 22
[0496] wherein Y and R.sub.8 are as defined above for Formula
I.
[0497] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0498]
4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2l.su-
p.4-benzo[1,2,6]thiadiazin-3-ylmethyl]-benzoic acid;
[0499]
4-[2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2l.sup.4-benzo-
[1,2,6]thiadiazin-3-ylmethyl]-benzoic acid; and
[0500]
4-[1-methyl-2,2,4-trioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2l-
.sup.6-benzo[1,2,6]thiadiazin-3-ylmethyl]-benzoic acid.
[0501] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 23
[0502] wherein Y and R.sub.8 are as defined above for Formula
I.
[0503] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0504]
3-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2l.su-
p.4-pyrido[3,4-c][1,2,6]thiadiazin-3-ylmethyl]-benzoic acid;
[0505]
3-[2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2l.sup.4-pyrid-
o[3,4-c][1,2,6]thiadiazin-3-ylmethyl]-benzoic acid; and
[0506]
3-[1-methyl-2,2,4-trioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2l-
.sup.6-pyrido[3,4-c][1,2,6]thiadiazin-3-ylmethyl]-benzoic acid.
[0507] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 24
[0508] wherein --, R.sub.6 and R.sub.7 are as defined above for
Formula I.
[0509] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0510]
4-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-1l.sup.4-benzo[e][1,2]thiazin--
2-ylmethyl]-benzoic acid; and
[0511]
4-[1,1-dioxo-7-(3-phenyl-prop-1-ynyl)-1H-1l.sup.6-benzo[e][1,2]thia-
zin-2-ylmethyl]-benzoic acid.
[0512] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 25
[0513] wherein --, R.sub.6 and R.sub.7 are as defined above for
Formula I.
[0514] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0515] 4-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-1l.sup.4-
thia-2,6-diaza-naphthalen-2-ylmethyl]-benzoic acid; and
[0516] 4-[1,1-dioxo-7-(3-phenyl-prop-1-ynyl)-1H-1l.sup.6-
thia-2,6-diaza-naphthalen-2-ylmethyl]-benzoic acid.
[0517] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 26
[0518] wherein R.sub.8 is as defined above for Formula I.
[0519] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0520]
4-[4-methyl-1,3-dioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1l.su-
p.4-thia-2,4,6-triaza-naphthalen-2-ylmethyl]-benzoic acid;
[0521]
4-[1,3-dioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1l.sup.4-thia--
2,4,6-triaza-naphthalen-2-ylmethyl]-benzoic acid; and
[0522]
4-[4-methyl-1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1l-
.sup.6-thia-2,4,6-triaza-naphthalen-2-ylmethyl]-benzoic acid.
[0523] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 27
[0524] wherein X and R.sub.8 are as defined above for Formula
I.
[0525] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0526]
4-[4-methyl-1,3-dioxo-6-(3-phenyl-prop-1-ynyl)3,4-dihydro-1H-1l.sup-
.4-thieno[2,3-e][1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
[0527]
4-[1,3-dioxo-6-(3-phenyl-prop-1-ynyl)3,4-dihydro-1H-1l.sup.4-thieno-
[2,3-e][1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
[0528]
4-[4-methyl-1,1,3-trioxo-6-(3-phenyl-prop-1-ynyl)3,4-dihydro-1H-1l.-
sup.6-thieno[2,3-e][1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
[0529]
4-[1,1,3-trioxo-6-(3-phenyl-prop-1-ynyl)3,4-dihydro-1H-1l.sup.6-thi-
eno[2,3-e][1,2,4]thiadiazin-2-ylmethyl]-benzoic acid.
[0530] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 28
[0531] wherein --, X, R.sub.6, and R.sub.7 are as defined above for
Formula I.
[0532] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0533]
4-[1-oxo-6-(3-phenyl-prop-1-ynyl)-1H-1l.sup.4-thieno[2,3-e][1,2]thi-
azin-2-ylmethyl]-benzoic acid; and
[0534]
4-[1,1-dioxo-6-(3-phenyl-prop-1-ynyl)-1H-1l.sup.6-thieno[2,3-e][1,2-
]thiazin-2-ylmethyl]-benzoic acid.
[0535] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 29
[0536] wherein X and R.sub.7 are as defined above for Formula
I.
[0537] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0538]
4-[1,3-dioxo-6-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1l.sup.4-thien-
o[2,3-e][1,2]thiazin-2-ylmethyl]-benzoic acid; and
[0539]
4-[1,1,3-trioxo-6-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1l.sup.6-th-
ieno[2,3-e][1,2]thiazin-2-ylmethyl]-benzoic acid.
[0540] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 30
[0541] wherein X, Y, and R.sub.7 are as defined above for Formula
I.
[0542] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, named:
[0543]
4-[4,6-dioxo-2-(3-phenyl-prop-1-ynyl)-6,7-dihydro-4H-thieno[3,2-c]p-
yridin-5-ylmethyl]-benzoic acid.
[0544] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 31
[0545] wherein --, X, Y, R.sub.6, and R.sub.7 are as defined above
for Formula I.
[0546] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, named:
[0547]
4-[4-oxo-2-(3-phenyl-prop-1-ynyl)-4H-thieno[3,2-c]pyridin-5-ylmethy-
l]-benzoic acid.
[0548] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 32
[0549] wherein --, X, R.sub.6, and R.sub.7 are as defined above for
Formula I.
[0550] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0551]
4-[4-oxo-2-(3-phenyl-prop-1-ynyl)-4H-1,4l.sup.4-dithia-3,5-diaza-in-
den-5-ylmethyl]-benzoic acid; and
[0552]
4-[4,4-dioxo-2-(3-phenyl-prop-1-ynyl)-4H-1,4l.sup.6-dithia-3,5-diaz-
a-inden-5-ylmethyl]-benzoic acid.
[0553] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 33
[0554] wherein X and R.sub.7 are as defined above for Formula
I.
[0555] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0556]
4-[4,6-dioxo-2-(3-phenyl-prop-1-ynyl)-6,7-dihydro-4H-1,4l.sup.4-dit-
hia-3,5-diaza-inden-5-ylmethyl]-benzoic acid; and
[0557]
4-[4,4,6-trioxo-2-(3-phenyl-prop-1-ynyl)-6,7-dihydro-4H-1,4l.sup.6--
dithia-3,5-diaza-inden-5-ylmethyl]-benzoic acid.
[0558] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 34
[0559] wherein X, Y, and R.sub.7 are as defined above for Formula
I.
[0560] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, named:
[0561]
4-[4,6-dioxo-2-(3-phenyl-prop-1-ynyl)-6,7-dihydro-4H-thiazolo[4,5-c-
]pyridin-5-ylmethyl-benzoic acid.
[0562] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 35
[0563] wherein X and R.sub.8 are as defined above for Formula
I.
[0564] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, selected from:
[0565]
4-[7-methyl-4,6-dioxo-2-(3-phenyl-prop-1-ynyl)-6,7-dihydro-4H-1,4l.-
sup.4-dithia-3,5,7-triaza-inden-5-ylmethyl]-benzoic acid;
[0566]
4-[4,6-dioxo-2-(3-phenyl-prop-1-ynyl)-6,7-dihydro-4H-1,4l.sup.4-dit-
hia-3,5,7-triaza-inden-5-ylmethyl]-benzoic acid;
[0567]
4-[7-methyl-4,4,6-trioxo-2-(3-phenyl-prop-1-ynyl)-6,7-dihydro-4H-1,-
4l.sup.6-dithia-3,5,7-triaza-inden-5-ylmethyl]-benzoic acid;
and
[0568]
4-[4,4,6-trioxo-2-(3-phenyl-prop-1-ynyl)-6,7-dihydro-4H-1,4l.sup.6--
dithia-3,5,7-triaza-inden-5-ylmethyl]-benzoic acid.
[0569] Also preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein G.sub.1 and
G.sub.2 are as defined above and B is 36
[0570] wherein --, X, Y, R.sub.6, and R.sub.7 are as defined above
for Formula I.
[0571] More preferred is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, named:
[0572]
4-[4-oxo-2-(3-phenyl-prop-1-ynyl)-4H-thiazolo[4,5-c]pyridin-5-ylmet-
hyl]-benzoic acid.
[0573] Also preferred is a compound of Formula I selected from:
[0574]
N-(4-Cyano-benzyl)-3-(3-[1,2,3]-triazol-1-yl-prop-1-ynyl)-benzamide-
;
[0575]
N-(4-Cyano-benzyl)-3-(3-[1,2,3]-triazol-1-yl-prop-1-ynyl)-benzamide-
;
[0576]
4-({3-[3-(4-Chloro-phenyl)-prop-1-ynyl]-benzoylamino}-methyl)-benzo-
ic acid;
[0577]
4-({3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-benzoylamino}-methyl)-benzo-
ic acid;
[0578] 3-Phenylethynyl-N-(4-Sulfamoyl-benzyl)-benzamide;
[0579] N-(4-Cyano-benzyl)-3-phenylethynyl-benzamide;
[0580] 3-Phenethylethynyl-N-pyridin-4-yl-methyl-benzamide; and
[0581] 3-[[3-(3-Phenethylethynyl-benzoylamino]-methyl}-benzoic
acid; or a pharmaceutically acceptable salt thereof.
[0582] Also preferred is a compound of Formula I selected from:
[0583]
4-({[5-(3-Phenyl-prop-1-ynyl)-pyridine-3-carbonyl]-amino}-methyl)-b-
enzoic acid; and
[0584]
4-{[(Phenylethynyl-pyridine-2-carbonyl)-amino]-methyl}-benzoic
acid; or a pharmaceutically acceptable salt thereof.
[0585] Also preferred is a compound of Formula I selected from:
[0586]
4-[1-Methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2.lam-
bda..sup.4-benzo[1,2,6]thiadiazin-3-yl methyl]benzoic acid;
[0587]
4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-ynyl)-1,4-dihydro-2H-2.l-
ambda..sup.6-benzo[1,2,6]thiadiazin-3-ylmethyl]benzoic acid;
[0588]
4-[1,1,3-Trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1.lambda..s-
up.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
[0589]
2-(4-Methoxy-benzyl)-1,1-dioxo-7-(3-phenyl-prop-1-ynyl)-1,4-dihydro-
-2H-1.lambda..sup.6-benzo[1,2,4]thiadiazin-3-one; and
[0590]
4-[1,1,3-Trioxo-7-(4-phenyl-but-1-ynyl)-3,4-dihydro-1H-1.lambda..su-
p.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid; or a
pharmaceutically acceptable salt thereof.
[0591] A further embodiment of this invention is a pharmaceutical
composition comprising, a compound of Formula I, or a
pharmaceutically acceptable salt thereof, or a tautomer thereof,
admixed with a carrier, excipient, or diluent. Preferred
compositions comprise a compound of Formulas II, III, IV, V, VI, or
VII.
[0592] Another embodiment of this invention is a method for
inhibiting MMP-13 in an animal, comprising administering to the
animal an MMP-13 inhibiting amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, or a tautomer
thereof.
[0593] A further embodiment is a method for treating a disease
mediated by an MMP-13 enzyme, comprising administering to a patient
suffering from such a disease an effective amount of a compound of
Formula I, or a pharmaceutically acceptable salt thereof, or a
tautomer thereof.
[0594] A preferred method of treatment according to this invention
is treatment of a disease selected from cancer, especially breast
carcinoma, and inflammation and heart failure. Other diseases to be
treated according to preferred aspect of this invention include
rheumatoid arthritis and osteoarthritis.
[0595] Another preferred method of treatment according to this
invention is treatment of a disease selected from heart disease,
multiple sclerosis, arthritis, other than osteoarthritis and
rheumatoid arthritis, atherosclerosis, age-related macular
degeneration, chronic obstructive pulmonary disease, psoriasis,
asthma, cardiac insufficiency, inflammatory bowel disease,
periodontal diseases, and osteoporosis.
DETAILED DESCRIPTION OF THE INVENTION
[0596] The compounds provided by this invention are those defined
by Formula I, or a pharmaceutically acceptable salt thereof, or a
tautomer thereof. In groups G.sub.1, G.sub.2, and B of Formula I,
R.sub.1 to R.sub.8 include "C.sub.1-C.sub.6 alkyl" groups. These
are straight and branched carbon chains having from 1 to 6 carbon
atoms. Examples of such alkyl groups include methyl, ethyl,
isopropyl, tert-butyl, neopentyl, and n-hexyl. The alkyl groups can
be substituted if desired, with from 1 to 3 groups selected from
hydroxy, amino, alkylamino, and dialkylamino, halo,
trifluoromethyl, carboxy, nitro, and cyano.
[0597] Examples of NR.sub.1R.sub.2 or NR.sub.3R.sub.4 groups
include amino, methylamino, di-isopropylamino, acetyl amino,
propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino,
3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and
3-carboxypropionyl amino. R.sub.1 and R.sub.2, or R.sub.3 and
R.sub.4, can independently be taken together with the nitrogen to
which they are attached to form a ring having 3 to 7 carbon atoms
and 1, 2, or 3 heteroatoms selected from the group consisting of
nitrogen, substituted nitrogen, wherein substituted nitrogen is as
defined below, oxygen, and sulfur. Examples of such cyclic
NR.sub.1R.sub.2 or NR.sub.3R.sub.4 groups include pyrrolidinyl,
piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl,
piperidinyl, pyrazinal, morpholinyl, and the like.
[0598] "Amino" means NH.sub.2.
[0599] "Halo" includes fluoro, chloro, bromo, and iodo.
[0600] "Alkenyl" means straight and branched hydrocarbon radicals
having from 2 to 6 carbon atoms and one double bond and includes
ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the
like.
[0601] "Alkynyl" means straight and branched hydrocarbon radicals
having from 2 to 6 carbon atoms and one triple bond and includes
ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and
the like.
[0602] "Carbocycle" and "Cycloalkyl" mean a monocyclic or
polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl,
cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl,
decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can
be substituted with groups such as hydroxy, keto, and the like.
Also included are rings in which 1 to 3 heteroatoms replace
carbons. Such groups are termed "heterocycle" or "heterocyclyl",
which means a cycloalkyl group also bearing at least one heteroatom
selected from O, S, or NR.sub.2, examples being oxiranyl,
pyrrolidinyl, piperidyl, 4-methylpiperazinyl, tetrahydropyran, and
morpholine.
[0603] "Alkoxy" refers to the alkyl groups mentioned above bound
through oxygen, examples of which include methoxy, ethoxy,
isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers
to polyethers such as --O--(CH.sub.2).sub.2--O--CH.sub.3, and the
like.
[0604] "Alkanoyl" groups are alkyl linked through a carbonyl, ie,
C.sub.1-C.sub.5--C(O)--. Such groups include formyl, acetyl,
propionyl, butyryl, and isobutyryl.
[0605] "Acyl" means an alkyl or aryl (Ar) group bonded through a
carbonyl group, ie, R--C(O)--. For example, acyl includes a
C.sub.1-C.sub.6 alkanoyl, including substituted alkanoyl, wherein
the alkyl portion can be substituted by NR.sub.1R.sub.2 or a
carboxylic or heterocyclic group. Typical acyl groups include
acetyl, benzoyl, and the like.
[0606] The alkyl, alkenyl, alkoxy, and alkynyl groups described
above are optionally substituted, preferably by 1 to 3 groups
selected from NR.sub.1R.sub.2, phenyl, substituted phenyl,
heterocycle, thio C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, carboxy, C.sub.1-C.sub.6 alkoxycarbonyl, halo, nitrile,
cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic
ring having 1 or 2 heteroatoms selected from nitrogen, substituted
nitrogen, oxygen, and sulfur.
[0607] "Substituted nitrogen" means nitrogen bearing
C.sub.1-C.sub.6 alkyl or (CH.sub.2).sub.nPh where n is 1, 2, or 3.
Perhalo and polyhalo substitution is also embraced.
[0608] Examples of substituted alkyl groups include 2-aminoethyl,
pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl,
2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl,
methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl,
2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl,
pentafluoroethyl, benzyl(Bn), 3-morpholinopropyl,
piperazinylmethyl, pyridyl-4-methyl(Py-4-me),
3-(pyridyl-4-thio)propyl, and 2-(4-methylpiperazinyl)ethyl.
[0609] Examples of substituted alkynyl groups include
2-methoxyethynyl, 2-ethylsulfanyethynyl,
4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl,
3-diethylamino-3-butynyl, 4-chloro-3-butynyl,
4-cyclobutyl-4-hexenyl, and the like.
[0610] Typical substituted alkoxy groups include aminomethoxy,
trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy,
3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
[0611] Further, examples of substituted alkyl, alkenyl, and alkynyl
groups include dimethylaminomethyl, carboxymethyl,
4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl,
4-morpholinobutyl, 4-tetrahydropyrinidylbutyl,
3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl,
phenylmethyl, 3-chlorophenylmethyl, and the like.
[0612] The terms "Ar" and "aryl" refer to unsubstituted and
substituted aromatic groups. Heteroaryl groups have from 4 to 10
ring atoms, which are carbon atoms and from 1 to 4 of which are
independently selected from the group consisting of O, S, and N.
Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or
6-membered aromatic ring. Mono- and bicyclic aromatic ring systems
are included in the definition of aryl and heteroaryl. Typical aryl
groups include phenyl and naphthyl. Typical substituted aryl groups
include 2,4,6-tribromophenyl, 4,7-dichloronaphthyl, 3-chlorophenyl,
3,4-methylenedioxyphenyl, and 2,6-dibromophenyl. Typical heteroaryl
groups include pyridyl, benzothienyl, furanyl, indolyl,
benzotriazolyl, indazolyl, pyrrolyl, pyrazolyl, imidazolyl,
thiazolyl, and the like.
[0613] Typical substituted heteroaryl groups include
3-methylpyridyl, 4-thiopyridyl, 4-ethylbenzothienyl, and
3,4-diethylfuranyl.
[0614] Preferred Ar groups are phenyl and phenyl substituted by 1,
2, or 3 groups independently selected from alkyl, alkoxy, thio,
thioalkyl, heteroaryl, heterocyclyl, halo, hydroxy,--COOR.sub.9,
trifluoromethyl, nitro, amino of the formula --NR.sub.1R.sub.2, and
T(CH.sub.2).sub.mQR.sub.3 or T(CH.sub.2).sub.mCO.sub.2R.sub.3,
wherein m is 1 to 6; T is O, S, NR.sub.3, N(O)R.sub.3,
NR.sub.1R.sub.2Y, or CR.sub.1R.sub.2, Q is O, S, NR.sub.3,
N(O)R.sub.3, or NR.sub.1R.sub.2Y, wherein R.sub.1 and R.sub.2 are
as described above, and R.sub.9 is alkyl or substituted alkyl, for
example, methyl, trichloroethyl, diphenylmethyl, and the like. The
alkyl and alkoxy groups can be substituted as defined above. For
example, typical groups are carboxyalkyl, alkoxycarbonylalkyl,
hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl. Examples of
substituted phenyl are 3-methoxyphenyl, 4-(1H-tetrazol-5-yl)phenyl
2,6-dichlorophenyl, 3-nitrophenyl, 4-dimethylaminophenyl, and
biphenyl.
[0615] The phrase "tertiary organic amine" means a trisubstituted
nitrogen group wherein the 3 substituents are independently
selected from C.sub.1-C.sub.12 alkyl, C.sub.3-C.sub.12 cycloalkyl,
benzyl, or wherein two of the substituents are taken together with
the nitrogen atom to which they are attached to form a 5- or
6-membered, monocyclic heterocycle containing one nitrogen atom and
carbon atoms, and the third substituent is selected from
C.sub.1-C.sub.12 alkyl and benzyl, or wherein the three
substituents are taken together with the nitrogen atom to which
they are attached to form a 7- to 12-membered bicyclic heterocycle
containing 1 or 2 nitrogen atoms and carbon atoms, and optionally a
C.dbd.N double bond when 2 nitrogen atoms are present. Illustrative
examples of tertiary organic amine include triethylamine,
diisopropylethylamine, benzyl diethylamino,
dicyclohexylmethyl-amine, 1,8-diazabicycle[5.4.0]undec-7-ene (DBU),
1,4-diazabicyclo[2.2.2]octane (TED), and
1,5-diazabicycle[4.3.0]non-5-ene.
[0616] The term "comprising," which is synonymous with the terms
"including," "containing," or "characterized by," is inclusive or
open-ended, and does not exclude additional, unrecited elements or
method steps from the scope of the invention that is described
following the term.
[0617] The phrase "consisting of " is closed-ended, and excludes
any element, step, or ingredient not specified in the description
of the invention that follows the phrase.
[0618] The phrase "consisting essentially of" limits the scope of
the invention that follows to the specified elements, steps, or
ingredients, and those further elements, steps, or ingredients that
do not materially affect the basic and novel characteristics of the
invention.
[0619] The phrase "pharmaceutical composition" means a composition
suitable for administration in medical or veterinary use.
[0620] The term "admixed" and the phrase "in admixture" are
synonymous and mean in a state of being in a homogeneous or
heterogeneous mixture. Preferred is a homogeneous mixture.
[0621] The term "patient" means a mammal. Preferred patients are
humans, cats, dogs, cows, horses, pigs, and sheep.
[0622] The term "animal" means a mammal, as defined above.
Preferred animals include humans, cats, dogs, horses, pigs, sheep,
cows, monkeys, rats, mice, guinea pigs, and rabbits.
[0623] The phrase "anticancer effective amount" means an amount of
invention compound, or a pharmaceutically acceptable salt thereof,
or a tautomer thereof, sufficient to inhibit, halt, or cause
regression of the cancer being treated in a particular patient or
patient population. For example in humans or other mammals, an
anticancer effective amount can be determined experimentally in a
laboratory or clinical setting, or may be the amount required by
the guidelines of the United States Food and Drug Administration,
or equivalent foreign agency, for the particular cancer and patient
being treated.
[0624] The phrase "anti-arthritic effective amount" means an amount
of invention compound, or a pharmaceutically acceptable salt
thereof, or a tautomer thereof, sufficient to inhibit, halt, or
cause regression of the arthritis being treated in a particular
patient or patient population. For example in humans or other
mammals, an anti-arthritic effective amount can be determined
experimentally in a laboratory or clinical setting, or may be the
amount required by the guidelines of the United States Food and
Drug Administration, or equivalent foreign agency, for the
particular arthritis and patient being treated.
[0625] The phrase "MMP-13 inhibiting amount" means an amount of
invention compound, or a pharmaceutically acceptable salt thereof,
or a tautomer thereof, sufficient to inhibit an enzyme matrix
metalloproteinase-13, including a truncated form thereof, including
a catalytic domain thereof, in a particular animal or animal
population. For example in a human or other mammal, an MMP-13
inhibiting amount can be determined experimentally in a laboratory
or clinical setting, or may be the amount required by the
guidelines of the United States Food and Drug Administration, or
equivalent foreign agency, for the particular MMP-13 enzyme and
patient being treated.
[0626] It should be appreciated that determination of proper dosage
forms, dosage amounts, and routes of administration, is within the
level of ordinary skill in the pharmaceutical and medical arts, and
is described below.
[0627] The phrases "effective amount" and "therapeutically
effective amount" are synonymous and mean an amount of a compound
of the present invention, a pharmaceutically acceptable salt
thereof, or a solvate thereof, sufficient to effect an improvement
of the condition being treated when administered to a patient
suffering from a disease that is mediated by MMP-13 and optionally
from 0 to 12 additional MMP enzymes.
[0628] The term "IC.sub.50" means the concentration of test
compound required to inhibit activity of a biological target, such
as a receptor or enzyme, by 50%.
[0629] The term "tautomer" means a form of invention compound
existing in a state of equilibrium with an isomeric form of the
invention compound, wherein the invention compound is able to react
according to either form by virtue of the ability of the forms to
interconvert by isomerization in situ, including in a reaction
mixture, in an in vitro biological assay, or in vivo.
[0630] The term "(E)" means entgegen, and designates that the
conformation about the double bond to which the term refers is the
conformation having the two higher ranking substituent groups, as
determined according to the Cahn-Ingold-Prelog ranking system, on
opposite sides of the double bond. An (E) double bond is
illustrated below by the compound of Formula (W) 37
[0631] wherein the two higher-ranking substituents are groups A and
D.
[0632] The term "(Z)" means zusammen, and designates that the
conformation about the double bond to which the term refers is the
conformation having the two higher ranking substituent groups, as
determined according to the Cahn-Ingold-Prelog ranking system, on
the same side of the double bond. A (Z) double bond is illustrated
below by the compound of Formula (X) 38
[0633] wherein the two higher-ranking substituents are groups A and
D.
[0634] The phrase "inert atmosphere" means an atmosphere that
consists essentially of nitrogen gas, or argon gas, or mixtures
thereof.
[0635] It should be appreciated that the matrix metalloproteinases
include the following enzymes:
[0636] MMP-1, also known as interstitial collagenase,
collagenase-1, or fibroblast-type collagenase;
[0637] MMP-2, also known as gelatinase A or 72 kDa Type IV
collagenase;
[0638] MMP-3, also known as stromelysin or stromelysin-1;
[0639] MMP-7, also known as matrilysin or PUMP-1;
[0640] MMP-8, also known as neutrophil collagenase or
polymorphonuclear-type ("PMN-type") collagenase;
[0641] MMP-9, also known as gelatinase B or 92 kDa Type IV
collagenase;
[0642] MMP-10, also known as stromelysin-2;
[0643] MMP-11, also known as stromelysin-3;
[0644] MMP-12, also known as metalloelastase;
[0645] MMP-13, also known as collagenase-3;
[0646] MMP-14, also known as membrane-type ("MT") MMP-1 or
MT-MMP-1;
[0647] MMP-15, also known as MT-MMP-2;
[0648] MMP-16, also known as MT-MMP-3;
[0649] MMP-17, also known as MT-MMP-4;
[0650] MMP-18; and
[0651] MMP-19.
[0652] As discussed above, one aspect of the present invention is
novel compounds that are selective inhibitors of the enzyme MMP-13.
A selective inhibitor of MMP-13, as used in the present invention,
is a compound that is .gtoreq.5.times.more potent in vitro versus
MMP-13 than versus at least one other matrix metalloproteinase
enzyme such as, for example, MMP-1, MMP-2, MMP-3, MMP-7, MMP-8,
MMP-9, or MMP-14, or versus tumor necrosis factor alpha convertase
("TACE"). A preferred aspect of the present invention is novel
compounds that are selective inhibitors of MMP-13 versus MMP-1.
[0653] Some of the compounds of the present invention may exist as
tautomeric forms, which interchange via, for example, enolization
and the like. All tautomeric forms are within the scope of the
present invention.
[0654] Some compounds of the present invention have alkenyl groups,
which may exist as entgegen or zusammen conformations, in which
case all geometric forms thereof, both entgegen and zusammen, cis
and trans, and mixtures thereof, are within the scope of the
present invention.
[0655] Some compounds of the present invention have cycloalkyl
groups, which may be substituted at more than one carbon atom, in
which case all geometric forms thereof, both cis and trans, and
mixtures thereof, are within the scope of the present
invention.
[0656] The compounds to be used in the present invention can exist
in unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms, including hydrated forms,
are equivalent to unsolvated forms and are intended to be
encompassed within the scope of the present invention. Some of the
invention compounds may have one or more chiral centers, and as
such can exist as individual enantiomers and mixtures. This
invention contemplates all racemic mixtures, pure enantiomers, as
well as geometric and positional isomers.
[0657] The compounds of Formulas I to VII are capable of further
forming both pharmaceutically acceptable formulations comprising
salts, including but not limited to, acid addition and/or base
salts, solvents, and N-oxides of a compound of Formulas I to VII.
This invention also provides pharmaceutical formulations comprising
a compound of Formulas I to VII together with a pharmaceutically
acceptable carrier, diluent, or excipient therefor. All of these
forms can be used in the method of the present invention.
[0658] Pharmaceutically acceptable acid addition salts of the
compounds of Formulas I to VII include salts derived form inorganic
acids such as hydrochloric, nitric, phosphoric, sulfuric,
hydrobromic, hydriodic, phosphorus, and the like, as well as, the
salts derived from organic acids, such as aliphatic mono- and
dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy
alkanoic acids, alkanedioic acids, aromatic acids, aliphatic, and
aromatic sulfonic acids, etc. Such salts thus include sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate,
caprylate, isobutyrate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate,
methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate,
toluenesulfonate, phenylacetate, citrate, lactate, maleate,
tartrate, methanesulfonate, and the like. Also contemplated are the
salts of amino acids such as arginate, gluconate, galacturonate,
and the like; see, for example, Berge et al., "Pharmaceutical
Salts," J. of Pharmaceutical Science, 1977;66:1-19.
[0659] The acid addition salts of the basic compounds are prepared
by contacting the free base form with a sufficient amount of the
desired acid to produce the salt in the conventional manner. The
free base form may be regenerated by contacting the salt form with
a base and isolating the free base in the conventional manner. The
free base forms differ from their respective salt forms somewhat in
certain physical properties such as solubility in polar solvents,
but otherwise the salts are equivalent to their respective free
base for purposes of the present invention.
[0660] Pharmaceutically acceptable base addition salts are formed
with metals or amines, such as alkali and alkaline earth metal
hydroxides, or of organic amines. Examples of metals used as
cations are sodium, potassium, magnesium, calcium, and the like.
Examples of suitable amines are N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
N-methylglucamine, and procaine; see, for example, Berge et al.,
supra.
[0661] The base addition salts of acidic compounds are prepared by
contacting the free acid form with a sufficient amount of the
desired base to produce the salt in the conventional manner. The
free acid form may be regenerated by contacting the salt form with
an acid and isolating the free acid in a conventional manner. The
free acid forms differ from their respective salt forms somewhat in
certain physical properties such as solubility in polar solvents,
but otherwise the salts are equivalent to their respective free
acid for purposes of the present invention.
[0662] The compounds of the present invention can be formulated and
administered in a wide variety of oral and parenteral dosage forms,
including transdermal and rectal administration. All that is
required is that an MMP inhibitor be administered to a mammal
suffering from a disease in an effective amount, which is that
amount required to cause an improvement in the disease and/or the
symptoms associated with such disease. It will be recognized to
those skilled in the art that the following dosage forms may
comprise as the active component, a compound of Formula I or a
tautomer thereof, or a corresponding pharmaceutically acceptable
salt or solvate of a compound of Formula I, or a tautomer
thereof.
[0663] The invention compounds are prepared by methods well known
to those skilled in the art of organic chemistry. The compounds of
Formula I are prepared utilizing commercially available starting
materials, or reactants that are readily prepared by standard
organic synthetic techniques.
[0664] Further, syntheses of the compounds of the present invention
may utilize starting materials, intermediates, or reaction products
that contain a reactive functional group. A reactive functional
group may be protected during chemical reactions using protecting
groups that render the reactive groups substantially inert to the
reaction conditions. At a step in a synthesis of a compound of the
present invention subsequent to the chemical reaction requiring a
protecting group, and appropriate to the synthetic strategy
employed, the protecting group may be removed. See, for example,
Protective Groups in Organic Synthesis, 2.sup.nd ed., Greene T. W.
and Wuts P. G., John Wiley & Sons, New York, N.Y., 1991, which
is hereby incorporated by reference. Thus, for example, protecting
groups such as the following may be utilized to protect suitable
amino, hydroxyl, and other groups of related reactivity: carboxylic
acyl groups, such as formyl, acetyl, and trifluoroacetyl;
alkoxycarbonyl groups, such as ethoxycarbonyl, t-butoxycarbonyl
(BOC), and .beta.,.beta.,.beta.-trich- loroethoxycarbonyl (TCEC),
.beta.-iodoethoxycarbonyl; aryloxycarbonyl groups, such as
benzyloxycarbonyl (CBZ), p-methoxybenzyloxycarbonyl, and
phenoxycarbonyl; trialkyl silyl groups, such as trimethylsilyl and
t-butyldimethylsilyl (TBDMS); and groups such as trityl,
tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl,
diphenylphosphinyl, p-toluenesulfonyl, and benzyl may all be
utilized. The protecting group may be removed, after completion of
the synthetic reaction of interest, by procedures known to those
skilled in the art. For example, a BOC group may be removed by
acidolysis, a trityl group by hydrogenolysis, TBDMS by treatment
with fluoride ions, and TCEC by treatment with zinc. Use of
protecting groups in organic synthesis is well within the skill of
the average artisan.
[0665] The compounds of the present invention can be prepared
according to the various synthetic schemes that follow. Protecting
groups may be used when appropriate throughout many of the schemes.
Although specifically noted in certain schemes, the appropriate use
and choice of protecting groups is well known by one skilled in the
art, and is not limited to the specific examples below. It is also
understood that such groups not only serve to protect chemically
reactive sites, but also to enhance solubility or otherwise change
physical properties. A good general reference for protecting group
preparation and deprotection is "Protective Groups in Organic
Synthesis" by Theodora Green, supra. A number of general reactions
such as oxidations and reductions are not shown in detail but can
be done by methods understood by one skilled in the art. General
transformations are reviewed in "Comprehensive Organic
Transformation" by Richard Larock, and the series "Compendium of
Organic Synthetic Methods" (1989) published by
Wiley-Interscience.
[0666] It should be appreciated that reagents, solvents, and
starting materials necessary for the preparation of the compounds
of the invention may be purchased from a number of commercial
sources or may be readily prepared by a number of methods well
known to one of average skill in the art of organic chemistry.
Further, reactions used to prepare the invention compounds can be
carried out under a wide variety of conditions comprising solvents,
reagents, catalysts, temperatures, time, atmosphere, and
pressure.
[0667] Different methods may be used to prepare the invention
compounds. However for purposes of practicing the invention, which
comprises compounds, pharmaceutical compositions, and methods of
preventing or treating patients with the disorders or diseases
recited above, it does not matter how the compounds are made.
[0668] A compound of Formula I, or a pharmaceutically acceptable
salt thereof, may be prepared by one of ordinary skill in the art
of organic chemistry by adapting various synthetic procedures which
are well known in the art of organic chemistry. A wide variety of
synthetic procedures may be found in the literature in, for
example, Reagents for Organic Synthesis, by Fieser and Fieser, John
Wiley & Sons, Inc., New York, 2000; Comprehensive Organic
Transformations, by Richard C. Larock, VCH Publishers, Inc., New
York, 1989; the series Compendium of Organic Synthetic Methods
(1989) by Wiley-Interscience; and the text Advanced Organic
Chemistry, 5.sup.th edition, by Jerry March, Wiley-Interscience,
New York (2001). Synthetic procedures directed specifically to the
preparation of a wide variety of heterocycles may be found in the
Handbook of Heterocyclic Chemistry, by Alan R. Katritzky, Pergamon
Press Ltd., London, (1985).
[0669] Alternatively, a skilled artisan may find methods useful for
preparing the invention compounds in the chemical literature by
searching widely available databases such as, for example, those
available from the Chemical Abstracts Service, Columbus, Ohio, or
MDL Information Systems GmbH (formerly Beilstein Information
Systems GmbH), Frankfurt, Germany. These databases may be searched
using keywords or structures, including structures of reactants
and/or reaction products.
[0670] Preparations of the compounds of the present invention may
use starting materials, reagents, solvents, and catalysts that may
be purchased from commercial sources or they may be readily
prepared by adapting procedures in the references or resources
cited above. Commercial sources of starting materials, reagents,
solvents, and catalysts useful in preparing invention compounds
include, for example, The Aldrich Chemical Company, and other
subsidiaries of Sigma-Aldrich Corporation, St. Louis, Mo., BACHEM,
BACHEM A. G., Switzerland, or Lancaster Synthesis Ltd., United
Kingdom.
[0671] Particularly, compounds of Formula I may be prepared
according to the synthetic route outlined in Scheme 1. 39
[0672] In Scheme I, a compound of formula (A), wherein Q is
hydrogen and G.sub.I is as defined above for Formula I, is allowed
to react with a compound of formula (B), wherein LG is a leaving
group selected from Cl, Br, I, and CF.sub.3SO.sub.3, and G.sub.2
and B are as defined above for Formula I, in the presence of a
suitable coupling reagent such as a palladium catalyst, including
bis(triphenylphosphinyl) palladium chloride palladium tetrakis
triphenylphosphine, palladium acetate, or palladium chloride, in
the presence of a base such as a tertiary organic amine, including
triethylamine or diisopropylethylamine, or potassium acetate in a
suitable aprotic solvent such as tetrahydrofuran ("THF"), heptane,
or ethyl acetate to yield a compound of Formula I, wherein G.sub.1,
G.sub.2, and B are as defined above for Formula I. This coupling
reaction works for a variety of B groups, including aryl or
heteroaryl B groups. See Comprehensive Organic Transformations, by
Richard C. Larock, VCH Publishers, Inc, New York, 1989:302-303 and
references cited therein; and Advanced Organic Chemistry by Jerry
March, John Wiley & Sons, New York, 4.sup.th edition,
1992:717-718, and references cited therein.
[0673] Alternatively in Scheme 1, a compound of formula (A),
wherein Q is a metal derivative such as ZnC1, Mg-(C1, Br, or I)
SnR.sub.3, wherein R is C.sub.1-C.sub.6 alkyl, such as n-butyl, or
Cu, and G.sub.1 is as defined above for Formula I, is allowed to
react with a compound of formula (B), wherein LG is a leaving group
selected from Cl, Br, I, and CF.sub.3SO.sub.3, and G.sub.2 and B
are as defined above for Formula I, in the presence of a palladium
catalyst as defined immediately above in a suitable solvent such as
heptane, THF, and the like, to give a compound of Formula I,
wherein G.sub.1, G.sub.2, and B are as defined above for Formula
I.
[0674] Alternatively in Scheme 1, a compound of formula (A) wherein
Q is Br or I and G.sub.1 is as defined above for Formula I, is
allowed to react with a compound of formula (B), wherein LG is a Cu
(I) derivative such as Cu.sup.+, hemi Cu.sup.+/hemi Li.sup.+, or
CuCNLi, in a solvent such as THF, ethyl ether, heptane, and the
like to give a compound of Formula I wherein G.sub.1, G.sub.2, and
B are as defined above for Formula I (see La Rock, supra,
1989:305).
[0675] Compounds of formula (A), wherein Q is hydrogen or a metal
derivative as defined above for Scheme 1, may be prepared by a
number of methods well-known to an artisan of ordinary skill in the
organic chemistry art (see La Rock, supra, 1989;1057-1058), and
references cited therein. Examples of such methods are illustrated
in Scheme 2. 40
[0676] In Scheme 2, a compound of formula (C), wherein G.sub.1 is
as defined above for Formula I, is allowed to react with a compound
of Formula I, in the presence of potassium tertiary-butoxide (2 mol
equivalents) in a solvent such as THF, ethyl acetate, benzene, and
the like, followed by addition of water to give a compound of
formula (D). The compound of formula (D) is allowed to react with a
strong base such as n-butyl lithium, tertiary-butyl lithium, sodium
hydride, and the like, followed by reaction with a metal derivative
such as ZnCl.sub.2, a magnesium dihalide, wherein halide is
chloride, bromide, or iodide, a trialkyl tin chloride (e.g.,
tri(n-butyl)tin chloride), or copper (I) iodide to give a compound
of formula (A).
[0677] Alternatively in Scheme 2, the compound of formula (D) is
allowed to react with a strong base such a n-butyl lithium,
tertiary-butyl lithium, or sodium hydride, followed by reaction
with the intermediate so formed with bromine (or iodine) to give a
compound of formula (E). The compound of formula (E) is allowed to
react with zinc metal and a source of chloride to provide a
compound of formula (A) wherein Q is ZnCl, or the compound of
formula (E) is allowed to react with a base such as n-butyl lithium
followed by a metal derivative such as zinc chloride; a magnesium
dihalide, wherein halide is chloride, bromide, or iodide; trialkyl
tin chloride; or copper (I) iodide to give a compound of formula
(A), wherein Q is ZnCl, Mg(Cl, Br, or I).sub.2, SnR.sub.3, or Cu,
respectively.
[0678] A compound of formula (B) wherein LG, B, and G.sub.2 are as
defined above for Formula I may be prepared by methods that are
known to an artisan of ordinary skill in the synthetic organic
chemistry art or may be purchased from sources of commercial
organic compounds such as the Aldrich Chemical Company of
Milwaukee, Wis. Illustrative examples of the preparations of a
compound of formula (B) are outlined in Schemes 3 to 6. 41 42 43
44
[0679] In Scheme 3, a compound of formula (F), wherein B and
G.sub.2 are as defined above for Formula I, is allowed to react
with a base such as n-butyl lithium, sodium hydride, or potassium
hexamethyldisilazide ("KHMDS") in an aprotic solvent such as THF,
dimethylsulfoxide ("DMSO"), or heptane, followed by reaction of the
intermediate organometallic species which results with bromine or
iodine to give a compound of formula (B), wherein LG is Br or I,
respectively.
[0680] In Scheme 4, a compound of formula (G), wherein B and
G.sub.2 are as defined above for Formula I, is allowed to react
with trifluoromethanesulfonyl chloride in the presence of a
nonnucleophilic base such as sodium hydride, triethylamine,
pyridine, and the like, in an aprotic solvent to give a compound of
formula (B), wherein LG is CF.sub.3SO.sub.3.
[0681] In Scheme 5, a compound of formula (F) as described above is
allowed to react with a halogenating reagent such as
N-chlorosuccinimide ("NCS"), N-bromosuccinimide ("NBS"), iodine,
chlorine, bromine, SO.sub.2Cl.sub.2, Br.sub.2/CCl.sub.4, and the
like optionally in the presence of a catalyst such as AlCl.sub.3,
FeCl.sub.3, silica, alumina, or acetic acid to give a compound of
formula (B), wherein LG is Cl, Br, or I.
[0682] In Scheme 6, a compound of formula (G) as described above is
allowed to react with a halogenating reagent selected from
POCl.sub.3, POCl.sub.3/PCl.sub.5, PCl.sub.5, COCl.sub.2/PPh.sub.3,
or Br.sub.2/PPh.sub.3 to yield a compound of formula (B), wherein
LG is Cl or Br.
[0683] Compounds of formulas (F) and (G) may be prepared by methods
well known to an artisan of ordinary skill in the synthetic organic
chemistry art or purchased from commercial sources. For example,
these methods are described in Katristky, supra, 1985.
[0684] The following detailed examples further illustrate the
synthesis of typical invention compounds of Formula I. The examples
are representative only, and are not to be construed as limiting
the invention in any respect.
EXAMPLE 1
2-Benzyl-4-methyl-1,1-dioxo-7-(3-phenyl-prop-lynyl)-1,4-dihydro-2H-1l.sup.-
6-benzo[1,2,4]thiadiazin-3-one
[0685] 45
[0686] Step (1): N-(4-bromo-phenyl)-formamide 46
[0687] A 5-Liter round bottom flask was charged with acetic
anhydride (488 mL, 5.2 mol) and cooled to 0.degree. C. Formic acid
(240 mL, 6.4 mol) was then added at a rate that did not elevate the
temperature of the reaction mixture above 10.degree. C. After the
formic acid was added, the temperature of the reaction was raised
to 50-60.degree. C. and stirred for 3 hours. The reaction was then
cooled to 0.degree. C. and 400 mL of THF was added. A solution of
4-bromoaniline (344 g, 2.0 mol) in 800 mL of THF was added
dropwise. After the addition was complete, the reaction was allowed
to stir at this temperature for 4 hours. The reaction was checked
by thin-layer chromatography and found to be complete. The reaction
mixture was transferred to a round bottom flask and the solvent was
removed in vacuo. When the solvent had been removed, the residue
crystallized. The solid was triturated with heptane and filtered.
Obtained 396.8 grams of desired N-(4-bromo-phenyl)-formamide. Yield
99.2% The spectral properties of the solid were consistent with the
desired material.
[0688] Step (2): (4-bromo-phenyl)-methyl-amine 47
[0689] To a stirred 2M solution of borane methyl sulfide complex in
THF (580 mL, 1.16 mol) at 0.degree. C. was slowly added a solution
of N-(4-bromo-phenyl)-formamide (Example 1, Step (1), 93 g., 0.465
mol) in 280 mL of THF so that the temperature of the solution did
not rise above 5.degree. C. Once the addition of the formanilide
was complete, the reaction was brought to reflux and stirred for 3
hours. The reaction was then cooled to 0.degree. C. and 190 mL of
methanol was added slowly to control the frothing of the reaction.
Then hydrogen chloride gas was bubbled into the solution until the
pH was approximately 2. The solvents were removed in vacuo to
afford a solid. The solid was dissolved in water and the pH was
raised to 10, and the solution was extracted twice with ethyl
ether. The combined ether extracts were washed twice with brine and
dried over sodium sulfate. Removal of the ether solvent afforded
85.5 grams (98.8%) of (4-bromo-phenyl)-methyl-amine. The spectral
properties of the oil were consistent with the desired material.
High performance liquid chromatography ("HPLC") analysis revealed
that the oil was greater than 95% of 4-bromophenyl-N-methylaniline.
This material was used in the next step without purification.
[0690] Step (3):
7-Bromo-4-methyl-1,1-dioxo-1,4-dihydro-2H-1.sup.6-benzo[1-
,2,4]thiadiazin-3-one 48
[0691] To a stirred, cold (0.degree. C.) solution of
chlorosulfonylisocyanate (107 mL, 1.22 mol) in 200 mL of
nitromethane, was added a solution of 4-methylaminobromobenzene
(Example 1, Step (2), 188.6 g, 1.02 mol) in 700 mL of nitromethane,
dropwise over 30 minutes while keeping the temperature of the
reaction during the addition below 10.degree. C. The solution was
allowed to stir at 0.degree. C. for one hour and then aluminum
chloride (176.8 g, 1.33 mol) was added and the reaction was brought
to reflux and stirred for 2 hours. The reaction was cooled and
checked by TLC. No starting aniline remained. The solvent was
removed on the rotary evaporator and the thick, dark, gummy residue
was poured over ice. A gray clumpy solid formed. The clumps were
broken up and filtered and washed thoroughly with water. The solid
was then dissolved in 1N NaOH solution, and the solution was washed
twice with a 1:1 mixture of ether and ethyl acetate. The combined
organic extracts were then backwashed with 1N NaOH solution, and
the 1N NaOH solution was combined with the previous aqueous
extracts. The aqueous layer was cooled and then acidified to pH 3
by the addition of concentrated hydrochloric acid. A thick,
opalescent solid formed which was collected by filtration and
washed thoroughly with water. The off-white solid was dried in a
vacuum oven overnight at 50.degree. C. to afford 230 grams (77.4%)
of
7-bromo-4-methyl-1,1-dioxo-1,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-
-3-one.
[0692] Step (4):
2-Benzyl-7-bromo-4-methyl-1,1-dioxo-1,4-dihydro-2H-1l.sup-
.6-benzo[1,2,4]thiadiazin-3-one 49
[0693] To a solution of
7-bromo-4-methyl-1,1-dioxo-1,4-dihydro-2H-1l.sup.6-
-benzo[1,2,4]thiadiazin-3-one (Example 1, Step (3), 2.00 g, 6.87
mmol) in 30 mL of dimethylformamide was added
N,N-diisopropylethylamine (1.79 mL, 10.3 mmol). After stirring for
5 minutes, benzyl bromide (0.899 mL, 7.56 mmol) was added to the
reaction mixture. After stirring at room temperature for 24 hours,
to the resulting black solution was added 20 mL of H.sub.2O. The
precipitated product was filtered and washed with 10 mL of H.sub.2O
to give 2.45 g (93.5%) of 2-Benzyl-7-bromo-4-methyl-1,1-dioxo-
-1,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one: mp
155-157.degree. C.; IR (KBr) 3076, 1696, 1588, 1484, 1311, 1173
cm.sup.-1; .sup.1H NMR (400 MHz, DMSO-d.sub.6).delta.3.48 (s, 3H,
NCH.sub.3), 5.05 (s, 2H, NCH.sub.2Ar), 7.10 (d, J=9.03 Hz, 1H,
ArH), 7.23-7.27 (m, 3H, ArH), 7.43 (d, J=7.57 Hz, 2H, ArH), 7.73
(dd, J=5.86, 3.66 Hz, 1H, ArH), 8.02 (d, J=2.44 Hz, 1H, ArH);
MS(APCI+): m/z 381.0 (MH-). Anal. Calcd for
C.sub.15H.sub.13N.sub.2O.sub.3S.sub.1Br.sub.1: C, 47.26; H, 3.44;
N, 7.35. Found: C, 47.20; H, 3.45; N, 7.16.
[0694] Step (5): 2-benzyl-4-methyl-1,1-dioxo-7-(3-phenyl-prop-1
ynyl)-1,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one
[0695] To a solution of CuI (0.010 g, 0.052 mmol) and Pd
(PhCN).sub.2Cl.sub.2 (0.030 g, 0.079 mmol), (after purging with
nitrogen for 5 min) in 26 mL of anhydrous dioxane was added
P(t-Bu).sub.3 (0.032 g, 0.157 mmol), HN(i-Pr).sub.2 (1.10 mL, 7.87
mmol), 3-phenyl-1-propyne (0.979 mL, 7.87 mmol), and
2-benzyl-7-bromo-4-methyl-1,1-dioxo-1,4-dihydr-
o-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one (Example 1, Step (4),
1.00 g, 2.62 mmol). Under a nitrogen atmosphere, the reaction
mixture was stirred at room temperature for 24 hours. After the
reaction was completed, ethyl acetate (50 mL) was added and white
solids (H.sub.2N(I--Pr).sub.2Br) were filtered through celite. The
filtrate was concentrated and triturated with diethyl ether to give
0.800 g (73.4%) of 2-benzyl-4-methyl-1,1-dioxo-
-7-(3-phenyl-prop-lynyl)-1,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3--
one as a yellow solid: mp 125-127.degree. C.; IR (KBr) 3031, 2868,
1693, 1606, 1499, 1333, 1174 cm.sup.-1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.3.49 (s, 3H, NCH.sub.3), 3.84 (s, 2H,
CCH.sub.2Ar), 5.05 (s, 2H, NCH.sub.2Ar), 7.15 (d, J=8.80 Hz, 1H,
ArH), 7.24-7.44 (m, 10H, ArH), 7.67 (dd, J=8.00, 2.00 Hz, 1H, ArH),
7.97 (d, J=1.95 Hz, 1H, ArH); MS(APCI+): m/z 417.2 (MH.sup.+).
Anal. Calcd for C.sub.24H.sub.20N.sub.2O.sub.3S.sub- .1: C, 69.21;
H, 4.84; N, 6.73. Found: C, 69.17; H, 4.86; N, 6.55.
EXAMPLE 2
4-[4-Methyl-1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1l.sup.6--
benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid
[0696] 50
[0697] Step (1):
4-(7-Bromo-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l.sup.6--
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester
51
[0698] To a solution of 7-bromo-4-methyl-1,1-dioxo-1,4-dihydro-2H-
1l.sup.6-benzo[1,2,4]thiadiazin-3-one (Example 1, Step (3), 2.00 g,
6.87 mmol) in 7 mL of dimethylformamide was added
N,N-diisopropylethylamine (0.658 mL, 3.78 mmol). After stirring for
5 minutes, 4-bromomethyl-benzoic acid tert-butyl ester (1.02 g,
3.78 mmol) was added to the reaction mixture. After stirring at
room temperature for 48 hours, the black solution was concentrated
to give a brown oil. The product was purified by flash column
chromatography on silica gel (20% ethyl acetate:hexanes) and
triturated with diethyl ether to give 1.20 g (72.7%) of
4-(7-bromo-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l.sup.6-benzo[1,2,4]t-
hiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester as a white
solid: mp 120-122.degree. C.; IR (KBr)2989, 1688,1590,1480,1351,
1163 cm.sup.-1; .sup.1HNMR (400 MHz, CDCl.sub.3).delta.3.48 (s, 3H,
NCH.sub.3), 5.08 (s, 2H, NCH.sub.2Ar), 7.12 (d, J=8.80 Hz, ArH),
7.47 (d, J=8.30 Hz, 2H, ArH), 7.76 (d, J=8.80, 2.20 Hz, 1H, ArH),
7.93 (d, J=8.30 Hz, 2H, ArH), 8.02 (d, J=2.4 Hz, 1H, ArH);
MS(APCI+). Anal. Calcd for
C.sub.20H.sub.21N.sub.2O.sub.5S.sub.1Br.sub.1: C, 49.8; H, 4.42; N,
5.82. Found: C, 49.90; H, 4.40; N, 5.82.
[0699] Step (2):
4-[4-Methyl-1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dih-
ydro-1H-1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid
tert-butyl ester 52
[0700] To a solution of CuI (0.002 g, 0.013 mmol) and Pd
(PhCN).sub.2Cl.sub.2 (0.007 g, 0.019 mmol), (after purging with
nitrogen for 5 min) in 6 mL of anhydrous dioxane, was added
P(t-Bu).sub.3 (0.008 g, 0.037 mmol), HN(i-Pr).sub.2 (0.262 mL, 1.87
mmol), 3-phenyl-1-propyne (0.230 mL, 1.87 mmol), and
4-(7-bromo-4-methyl-1,1,3-trioxo-3,4-dihydro-1-
H-1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid
tert-butyl ester (Example 2, Step (1), 0.300 g, 0.623 mmol). Under
a nitrogen atmosphere, the reaction mixture was stirred at room
temperature for 24 hours. After the reaction was completed, ethyl
acetate (20 mL) was added and white solids,
(H.sub.2N(I--Pr).sub.2Br) were filtered through celite. The
filtrate was concentrated. The product was purified by flash column
chromatography on silica gel (10% ethyl acetate:hexanes) and
concentrated to give 0.200 g (62.1%) of
4-[4-methyl-1,1,3-trioxo-7-(3-phenyl-prop-1-yn-
yl)-3,4-dihydro-1H-1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic
acid tert-butyl ester as a yellow gel: 1H NMR (400 MHz, CDCl.sub.3)
.delta.1.99 (s, 3H, NCH.sub.3), 3.79 (s, 2H, CCH.sub.2Ar), 5.03 (s,
2H, NCH.sub.2Ar), 7.12 (d, J=8.80 Hz, 1H, ArH), 7.22 (t, J=2.20 Hz,
1H, ArH), 7.24-7.36 (m, 4H, ArH), 7.41 (d, J=8.30 Hz, 2H, ArH),
7.63 (dd, J=8.70, 2.00, 1H, ArH), 7.87 (d, J=8.30 Hz, 2H, ArH),
7.92 (d, J=2.00, 1H, ArH); MS(APCI+): m/z 461.3 (MH.sup.+).
[0701] Step (3):
4-[4-methyl-1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dih-
ydro-1H-1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid
53
[0702] To a solution of
4-[4-methyl-1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)--
3,4-dihydro-1H-1l.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic
acid tert-butyl ester in 2 mL of CH.sub.2Cl.sub.2 was added 2 mL of
trifluoroacetic acid. After stirring at room temperature for 24
hours, the reaction mixture was concentrated affording a yellow
oil. Trituration with 10 mL of diethyl ether gave 0.040 g (88.8%)
of
4-[4-methyl-1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1l.sup.6-
-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid as a light yellow
solid: mp 208-209.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.3.43 (s, 3H, NCH.sub.3), 3.89 (s, 2H, CCH.sub.2Ar), 5.00 (s,
2H, NCH.sub.2Ar), 7.22 (t, J=7.32 Hz, 1H, ArH), 7.30-7.33 (m, 2H,
ArH), 7.37-7.40 (m, 4H, ArH), 7.53 (d, J=8.79 Hz, 1H, ArH),
7.82-7.85 (m, 3H, ArH), 7.87 (d, J=8.30 Hz, 2H, ArH), 7.92 (d,
J=2.00, 1H, ArH), 11.0 (s, 1H, OH); MS(APCI+): m/z 459.1
(MH.sup.-).
EXAMPLE 3
2-Benzyl-1,1-dioxo-7-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-1l.sup.6-benzo[-
1,2,4]thiadiazin-3-one
[0703] Step (1): Synthesis of
7-iodo-1,1-dioxo-1,4-dihydro-2H-1l.sup.6benz-
o[1,2,4]thiadiazin-3-one
[0704] The procedure of Example 2, Step (3) was followed, except
that 4-iodoaniline was substituted for 4-methylaminobromobenzene,
to provide
7-iodo-1,1-dioxo-1,4-dihydro-2H-1l.sup.6benzo[1,2,4]thiadiazin-3-one;
.sup.1H-NMR (DMSO-d.sub.6); d 11.32 (s, 1H), 7.95 (d, 1H), 7.90
(dd, 1H), and 7.02 (d, 1H) ppm.
[0705] MS: M.sup.+1=322.9 Da
[0706] Step (2): Synthesis of
2-benzyl-7-iodo-1,1-dioxo-1,4-dihydro-2H-1l.-
sup.6-benzo[1,2,4]thiadiazin-3-one
[0707]
7-Iodo-1,1-dioxo-1,4-dihydro-2H-1l.sup.6benzo[1,2,4]thiadiazin-3-on-
e (3.5 g, 10.8 mmoles) was mixed with 1.61 mL of
1,8-diazabicyclo[5.4.0]un- dec-7-ene in 100 mL of acetonitrile at
room temperature. This was stirred for 30 minutes, and then 1.28 mL
of benzyl bromide was added. The resulting mixture was stirred
overnight. The reaction was concentrated in vacuo, and the residue
was partitioned between 1M HCl and dichloromethane. The organic
layer was dried (magnesium sulfate), filtered and concentrated to
give a purple oil. Chromatography (silica gel, 30% ethyl acetate in
hexanes) gave 1.02 g of 2-benzyl-7-iodo-1,1-dio-
xo-1,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one;
.sup.1H-NMR (DMSO-d.sub.6); d 11.56 (s, 1H), 8.10 (d, 1H), 8.01
(dd, 1H), 7.29 (m, 5H), 7.07 (d, 1H), and 4.93 (s, 2H) ppm. MS:
M.sup.+-1=413.0 Da
[0708] Step (3): Synthesis of
2-benzyl-1,1-dioxo-7-(3-phenyl-prop-1-ynyl)--
1,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one
2-Benzyl-7-iodo-1,1-dioxo-1,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin--
3-one (0.42 g, 1 mmol) was mixed with 0.13 mL of 3-phenylpropyne in
25 mL of N,N-dimethylformamide at room temperature.
Diisopropylethylamine (0.71 mL, 4.1 mmol) was added along with 0.04
g bis(triphenylphosphine)palladiu- m (II)dichloride (5 mol %) and a
catalytic amount of copper(I)iodide. The resulting mixture was
heated to 50.degree. C. for 3 hours, cooled to room temperature,
and stirred overnight. The reaction was partitioned between 1M HCl
and ethyl acetate. The organic layer was dried (magnesium sulfate),
filtered, and concentrated to give a yellow oil. Chromatography
(silica gel, 10% ethyl acetate/hexanes) gave
2-benzyl-1,1-dioxo-7-(3-phen-
yl-prop-1-ynyl)-1,4-dihydro-2H-1l.sup.6-benzo[1,2,4]thiadiazin-3-one
as a tan solid; .sup.1H-NMR (CDCl.sub.3); d 9.39 (bs, 1H), 7.92 (s,
1H), 7.57 (dd, 1H), 7.35 (m, 10H), 6.87 (d, 1H), 5.06 (s, 2H), and
3.82 (s, 2H) ppm. MS: M.sup.++1=403.1 Da
EXAMPLE 4
N-(4-Cyano-benzyl)-3-(3-[1,2,3]-triazol-1-yl-prop-1-ynyl)-benzamide
[0709] 54
[0710] Step (1): N-(4-Cyano-benzyl)-3-iodo-benzamide 55
[0711] An aliquot of 3-iodobenzoyl chloride (1.1 g, 4.2 mmol) was
taken up in tetrahydrofuran ("THF", 25 mL), and cooled to
approximately 0.degree. C. in an ice-water bath. To the cold
solution were added 4-cyanobenzylamine hydrochloride (0.71 g, 4.2
mmol) and pyridine (0.66 g, 8.3 mmol). The solution gradually
warmed to room temperature, and was stirred for 72 hours. The
reaction mixture was diluted with ethyl acetate (25 mL) and aqueous
HCl (25 mL). The organic phase was separated, dried (MgSO4),
filtered, and rotary evaporated. The resulting crude product was
purified using silica gel chromatography (elution with
dichloromethane/THF [9:1]) to give
N-(4-cyano-benzyl)-3-iodo-benzamide (0.76 g, 51%) as a white solid.
.sup.1H-NMR (DMSO-d.sub.6) .delta.9.2 (t, 1H), 8.2 (s, 1H), 7.9 (m,
2H), 7.8 (d, 2H), 7.5 (d, 2H), 7.3 (m, 1H), 4.5 (d, 2H) ppm.
[0712] Step (2):
N-(4-Cyano-benzyl)-3-([1,2,3]-triazol-1-yl-prop-1-ynyl)-b-
enzamide
[0713] A solution of 1-propyn-3-yl-1H-[1,2,3]triazol (0.086 g, 0.8
mmol) in N,N-dimethylformamide ("DMF", 1 mL) was treated with the
N-(4-cyano-benzyl)-3-iodo-benzamide (0.225 g, 0.62 mmol) prepared
in Step (1), diisopropylethylamine (0.32 g, 2.5 mmol), copper (I)
iodide (0.024 g, 0.013 mmol), and
dichlorobis(triphenylphosphine)palladium (II) (0.025 g, 0.004
mmol), respectively. The reaction mixture was stirred under
nitrogen atmosphere for 5 hours at 55.degree. C., then cooled to
room temperature. The crude reaction mixture was diluted with THF
(5 mL) and passed through a pad of silica gel (elution with THF).
The partially purified product obtained was further purified using
silica gel chromatography (elution with THF/hexane [3:1]) to give
the title compound (0.077 g, 36%) as cream color solid. .sup.1H-NMR
(CDCl.sub.3/DMSO-d.sub.6- ) .delta.8.3 (m, 1H), 7.9 (s, 1H), 7.8
(m, 2H), 7.6 (s, 1H), 7.4 (m, 3H), 7.3 (m, 2H), 5.3 (s, 2H), 4.5
(d, 2H) ppm. Mp 145.degree. C.-147.degree. C.
EXAMPLE 5
N-(4-Cyano-benzyl)-3-(3-[1,2,3]-triazol-1-yl-prop-1-ynyl)-benzamide
[0714] 56
[0715] Replacing the 1-propyn-3-yl-1H-[1,2,3]triazole in Example 4,
Step (2) with 1-propyn-3-yl-1H-[1,2,4]triazole yielded
N-(4-cyano-benzyl)-3-(3-
-[1,2,3]-trizol-1-yl-prop-1-ynyl)-benzamide; .sup.1H-NMR
(CDCl.sub.3/DMSO-d.sub.6) .delta.8.6 (s, 1H), 8.2 (t, 1H), 8.0 (s,
1H), 7.9 (s, 1H), 7.8 (m, 1H), 7.5 (m, 3H), 7.4 (m, 3H), 5.1 (s,
2H), 4.6 (d, 2H) ppm. Mp 183-186.degree. C.
EXAMPLE 6
4-{[3-(3-Phenethylethynyl-benzoylamino]-methyl}-benzoic acid
[0716] 57
[0717] Replacing 4-cyanobenzylamine hydrochloride in Example 4,
Step (1), with 4-carboxy-benzylamine hydrochloride, and replacing
the 1-propyn-3-yl-1H-[1,2,3]triazole in Example 4, Step (2), with
3-phenyl-propyne yielded
4-[[3-3-phenethylethynyl-benzoylamino]-methyl}-b- enzoic acid;
.sup.1H-NMR (DMSO-d.sub.6).delta.9.2 (m, 1H), 8.0 (s, 1H), 7.8 (m,
4H), 7.6 (d, 1H) 7.2-7.4 (m, 7H), 4.5 (d, 2H), 3.9 (s, 2H) ppm. Mp
209.degree. C.-211.degree. C.
[0718] By replacing the 4-cyanobenzylamine hydrochloride in Example
4, Step (1), with appropriately substituted amines and by
substituting for 1-propyn-3-yl-1H-[1,2,3]triazole in Example 4,
Step (2), with appropriately substituted alkynes, and by using the
experimental conditions outlined in Example 4, Steps (1) and (2),
respectively, the compounds of Examples 7 to 12 can be
synthesized.
EXAMPLE 7
4-({3-[3-(4-Chloro-phenyl)-prop-1-ynyl]-benzoylamino}-methyl)-benzoic
acid
[0719] 58
EXAMPLE 8
4-({3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-benzoylamino}-methyl)-benzoic
acid
[0720] 59
EXAMPLE 9
3-Phenylethynyl-N-(4-Sulfamoyl-benzyl)-benzamide
[0721] 60
EXAMPLE 10
N-(4-Cyano-benzyl)-3-phenylethynyl-benzamide
[0722] 61
EXAMPLE 11
3-Phenethlethynyl-N-pyridin-4-yl-methyl-benzamide
[0723] 62
EXAMPLE 12
3-[3-(3-Phenethylethynyl-benzoylamino)-methyl]-benzoic acid
[0724] 63
[0725] Replacement of 3-iodobenzoyl chloride in Example 4, Step
(1), with the appropriately substituted pyridine analog, and using
the experimental conditions outlined in Example 4, Steps (1) and
(2), the compounds of Examples 13 and 14 can be synthesized.
EXAMPLE 13
4-({[5-(3-Phenyl-prop-1-ynyl)-pyridine-3-carbonyl]-amino}-methyl)-benzoic
acid
[0726] 64
EXAMPLE 14
4-{[(Phenylethynyl-pyridine-2-carbonyl)-amino]-methyl}-benzoic
acid
[0727] 65
EXAMPLE 15
4-[1-Methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2.lambda..su-
p.4-benzo[1,2,6]thiadiazin-3-yl methyl]benzoic acid
[0728] Step (1): Synthesis of 5-Iodo-2-methlaminobenzoic acid
66
[0729] A suspension of N-methylanthranilic acid (10.00 g, 66.2
mmol) in glacial acetic acid (60 mL) was stirred at room
temperature for 20 minutes, then treated with water (120 mL). To
this was added iodine (16.80 g, 66.2 mmol) in portions, and the
reaction mixture was stirred vigorously for 5 days. The resulting
solid was collected by filtration, washed with water, and allowed
to air dry under house vacuum. Drying afforded 9.64 g of
5-iodo-2-methylaminobenzioc acid as green/brown solid (52.6%
yield). .sup.1H-NMR (DMSO-d.sub.6); d 7.95 (s, 1H), 7.58-7.56 (d,
1H), 6.52-6.50 (d, 1H), 2.78 (s, 3H). MS: M.sup.++1=277.9 Da
[0730] Step (2): Synthesis of
4-[5-iodo-2-methylaminobenzoylamino)methyl]b- enzoic acid
tert-butyl ester 67
[0731] A solution of 5-iodo-2-methylaminobenzoic acid (1.50 g, 5.4
mmol) in DMF (8 mL) was treated with 4-aminomethylbenzoic acid
tert-butyl ester (1.25 g, 6.50 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
("EDAC.HCl") (1.24 g, 6.50 mmol), 1-hydroxybenzotriazole hydrate
(0.88 g, 6.50 mmol), and the reaction mixture was stirred overnight
at room temperature. The resulting solution was treated with water
(15 mL), followed by saturated aqueous sodium bicarbonate (4 mL),
then water (15 mL), and the mixture was stirred for 30 minutes. The
aqueous/DMF layer was decanted from the resulting black gum, and
the gum was washed with water. The aqueous was decanted, and the
resulting material was dissolved in ethyl acetate, washed with
brine, dried over MgSO.sub.4 and evaporated onto silica gel.
[0732] The residue was purified on a 4.5.times.18 cm silica gel
column eluted with hexane/ethyl acetate 4:1. Evaporation and drying
afforded 2.10 g of
4-[5-iodo-2-methylaminobenzoylamino)methyl]benzoic acid tert-butyl
ester as a yellow foam (83.2% yield). .sup.1H-NMR (CDCl.sub.3); d
7.97-7.94 (m, 2H), 7.56-7.50 (m, 2H), 7.36-7.35 (d, 2H), 6.47-6.44
(d, 1H), 6.33 (bs, 1H), 4.60-4.59 (d, 2H), 2.82 (s, 1.57 (S, 9H).
MS: M.sup.++1=467.0 Da
[0733] Step (3): Synthesis of
4-[6-iodo-1-methyl-2,4-dioxo-1,4-dihydro-2H--
2.lambda..sup.4-benzol[1,2,6]thiadiazin-3yl methyl)benzoic acid
tert-butyl ester 68
[0734] A solution of
4-[5-iodo-2-methylaminobenzoylamino)methyl]benzoic acid tert-butyl
ester (1.73 g, 3.71 mmol) in benzene (60 mL) was treated with
thionyl chloride (0.30 mL, 4.08 mmol), then heated to reflux for 3
hours. The solution was diluted with benzene, washed with brine,
dried over MgSO.sub.4, and evaporated to dryness. The residue was
crystallized from hexane/ethyl acetate, and the crystals allowed to
air dry under house vacuum overnight. This afforded
4-[6-iodo-1-methyl-2,4-dioxo-1,4-di-
hydro-2H-2.lambda..sup.4-benzo[1,2,6]thiadiazin-3yl methyl)benzoic
acid tert-butyl ester as 1.64 g of yellow crystals (86.3% yield).
.sup.1H-NMR (CDCl.sub.3); d 8.50 (d, 1H), 7.97-7.96 (d, 2H), 7.94
(d, 1H), 7.41-7.38 (d, 2H), 6.78-6.75 (d, 1H), 5.41-5.37 (d, 1H),
4.75-4.71 (d, 1H), 3.36 (s, 3H), 1.56 (s, 9H). MS: M.sup.++1=512.9
Da
[0735] Step (4): Synthesis of
4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-yny-
l)-1,4-dihydro-2H-2.lambda..sup.4-benzo[1,2,6]thiadiazin-3yl
methyl]benzoic acid tert-butyl ester 69
[0736] A solution of
4-[6-iodo-1-methyl-2,4-dioxo-1,4-dihydro-2H-2.lambda.-
.sup.4-benzol[1,2,6]thiadiazin-3yl methyl)benzoic acid tert-butyl
ester (0.50 g, 0.98 mmol) in DMF (9 mL) in a screw cap vial was
degassed with nitrogen, then treated with triethylamine (0.56 mL,
4.0 mmol), CuI (0.013 g, 0.07 mmol), Pd(Ph.sub.3P).sub.4 (0.048 g,
0.042 mmol), and 3-phenyl-1-propyne (0.29 mL, 2.3 mmol). The
reaction mixture was heated in an oil bath at 65.degree. C. for 3
hours, cooled to room temperature, the DMF was evaporated, and the
residue dissolved in ethyl acetate. The organic portion was washed
with 1N HCl, brine, dried over MgSO.sub.4, and evaporated onto
silica gel
[0737] The silica gel mesh was purified on a 3.5.times.18 cm silica
gel column eluted with hexane/ethyl acetate 4: 1, followed by
hexane/ethyl acetate 2:1. Drying under high vacuum afforded the
product as 0.42 g of yellow foam (86.0% yield). .sup.1H-NMR
(CDCl.sub.3); d 8.29 (d, 1H), 7.96-7.94 (m, 2H), 7.68 (d, 1H),
7.42-7.34 (m, 6H), 7.27-7.24 (m, 1H), 6.94-6.92 (d, 1H), 4.76-4.72
(d, 1H), 3.82 (s, 2H), 3.38 (s, 3H), 1.57 (s, 9H). MS:
M.sup.+(-OtBu)+1=445.1 Da
[0738] Step (5): Synthesis of
4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-yny-
l)-1,4-dihydro-2H-2.lambda..sup.4-benzo[1,2,6]thiadiazin-3-yl
methyl]benzoic acid 70
[0739] A solution of
4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-di-
hydro-2H-2.lambda..sup.4-benzo[1,2,6]thiadiazin-3-yl methyl]benzoic
acid tert-butyl ester (0.33 g, 0.66 mmol) in methylene chloride (10
mL) was treated with trifluoroacetic acid (3 mL), and stirred at
room temperature for 1 hour. The reaction mixture was evaporated to
dryness, treated with hot ethyl acetate, allowed to cool, and the
solid collected by filtration. The solid was triturated with ethyl
ether, the solid collected by filtration, and allowed to air dry
under house vacuum. The process afforded 0.03 g of
4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-
-1,4-dihydro-2H-2.lambda..sup.4-benzo[1,2,6]thiadiazin-3-yl
methyl]benzoic acid as a blue/green solid (9.5% yield. .sup.1H-NMR
(CDCl.sub.3); d 8.30 (d, 1H), 8.08-8.06 (d, 2H), 7.69-7.67 (dd,
1H), 7.48-7.46 (d, 2H), 7.40-7.32 (m, 4H), 7.27-7.23 (m, 1H),
6.97-6.95 (d, 1H), 5.44-5.40 (d, 1H), 4.81-4.77 (d, 1H), 3.83 (s,
2H), 3.41 (s, 3H). MS: M.sup.++1=445.1 Da
EXAMPLE 16
4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-ynyl)-1,4-dihydro-2H-2.lambda..-
sup.6-benzo[1,2,6]-thiadiazin-3-ylmethyl]benzoic acid
[0740] Step (1): Synthesis of
4-[6-iodo-1-methyl-2,2,4-trioxo-1,4-dihydro--
2H-2.lambda..sup.4-benzo[1,2,6]-thiadiazin-3yl methyl)benzoic acid
tert-butyl ester 71
[0741] A suspension of
4-[6-iodo-1-methyl-2,2,4-trioxo-1,4-dihydro-2H-2.la-
mbda..sup.4-benzo[1,2,6]-thiadiazin-3yl methyl)benzoic acid
tert-butyl ester (0.60 g, 1.17 mmol) in ethyl acetate (5 mL) was
treated with an aqueous solution of>4% NaOCl (7.0 g), followed
by tetrabutylammonium bromide, and the reaction mixture stirred at
room temperature overnight. The reaction mixture was diluted with
water, extracted with ethyl acetate, the organic portion washed
with brine, dried over MgSO.sub.4, and evaporated to dryness to
give 0.61 g of white foam (98.6% yield)..sup.1H-NMR (CDCl.sub.3); d
8.47-8.46 (d, 1H), 7.95-7.91 (m, 3H), 7.00-6.97 (d, 1H), 5.21 (s,
2H), 3.30 (s, 3H), 1.55 (s, 9H). MS: M.sup.+(--O-tBu)+1=472.9
Da
[0742] Step (2): Synthesis of
4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-y-
nyl)-1,4-dihydro-2H-2.lambda..sup.6-benzo[1,2,6]-thiadiazin-3-ylmethyl]ben-
zoic acid tert-butyl ester 72
[0743] The coupling of
4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-ynyl)-1,-
4-dihydro-2H-2.lambda..sup.6-benzo[1,2,6]-thiadiazin-3-ylmethyl]benzoic
acid tert-butyl ester (0.60 g, 1.13 mmol) with 3-phenyl-1-propyne
(0.33 mL, 2.65 mmol) using triethylamine (0.64 mL, 4.51 mmol), CuI
(0.015 g, 0.08 mmol), and Pd(Ph.sub.3P).sub.4 (0.055 g, 0.047 mmol)
was carried out as described in Example 15, Step (4). Purification
on a silica gel column eluted with hexane/ethyl acetate 4:1,
followed by drying, afforded 0.10 g of
4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-ynyl)-1,4-dihydro-2H-2.lamb-
da..sup.6-benzo[1,2,6]-thiadiazin-3-ylmethyl]benzoic acid
tert-butyl ester as a white foam (17.0% yield). .sup.1H-NMR
(CDCl.sub.3); d 8.23-8.22 (d, 1H), 9.95-7.93 (d, 2H), 7.68 (d, 1H),
7.51-7.49 (d, 2H), 7.38-7.30 (m, 3H), 7.27-7.23 (m, 1H), 7.17-7.16
(d, 2H), 5.13 (s, 2H), 3.82 (s, 2H), 3.32 (s, 3H), 1.55 (s, 9H).
MS: M.sup.+(--O-tBu)+1=461.1 Da
[0744] Step (3): Synthesis of
4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-y-
nyl)-1,4-dihydro-2H-2.lambda..sup.6-benzo[1,2,6]-thiadiazin-3-ylmethyl]ben-
zoic acid 73
[0745] A solution of
4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-ynyl)-1,4--
dihydro-2H-2.lambda..sup.6-benzo[1,2,6]-thiadiazin-3-ylmethyl]benzoic
acid tert-butyl ester (0.075 g, 0.15 mmol) was treated with
trifluoroacetic acid (5 mL), and the reaction mixture stirred at
room temperature for 30 minutes. The solution was evaporated to
dryness, the residue dissolved in ethyl acetate, washed with water,
brine, and dried over MgSO.sub.4, and evaporated. Trituration with
ethyl ether afforded a solid that was collected by filtration,
washed with ethyl ether, and allowed to air dry under hose vacuum
overnight. This afforded 0.015 g of
4-[1-methyl-2,2,4-trioxo-6-(3-phenylprop-1-ynyl)-1,4-dihydro-2H-2.lambda.-
.sup.6-benzo[1,2,6]-thiadiazin-3-ylmethyl]benzoic acid as a light
yellow solid (23.2% yield). .sup.1H-NMR (CDCl.sub.3); d 8.24 (d,
1H), 8.08-8.05 (d, 2H), 7.69-7.66 (dd, 1H), 7.57-7.55 (d, 2H),
7.38-7.31 (m, 4H), 7.27-7.23 (m, 1H), 7.18-7.16 (d, 1H), 5.16 (s,
2H), 3.34 (s, 3H). MS: M.sup.++1=461.1 Da
EXAMPLE 17
4-[1,1,3-Trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1.lambda..sup.6-be-
nzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid
[0746] Step (1): Synthesis of
4-[(2-Nitro-benzenesulfonylamino)-methyl]-be- nzoic acid tert-butyl
ester 74
[0747] 2-Nitro-benzenesulfonyl chloride (8.55 g, 38.6 mmol) and
4-aminomethyl-benzoic acid tert-butyl ester (8.0 g, 38.6 mmol) were
mixed in 400 mL of dichloromethane. Triethylamine (10.8 mL, 77.2
mmol) was added, and the resulting mixture was stirred at room
temperature for 16 hours. The reaction was partitioned between 1M
HCl and dichloromethane. The organic layer was dried (magnesium
sulfate), filtered, and rotary evaporated to give 14.46 g (95%) of
4-[(2-nitro-benzenesulfonylamino)-met- hyl]-benzoic acid tert-butyl
ester as an off-white solid. .sup.1H-NMR (CDCl.sub.3); .delta.8.00
(dd, 1H), 7.84 (m, 3H), 7.67 (m, 2H), 7.27 (dd, 2H), 5.76 (bt, 1H),
4.36 (d, 2H), and 1.57 (s, 9H). MS: M.sup.+=392.1 Da
[0748] Step (2): Synthesis of
4-[(2-Amino-benzenesulfonylamino)-methyl]-be- nzoic acid tert-butyl
ester 75
[0749] 4-[(2-Nitro-benzenesulfonylamino)-methyl]-benzoic acid
tert-butyl ester (14.4 g, 40 mmol) was dissolved in 100 mL of
tetrahydrofuran containing 10 g of Raney Nickel. The reaction was
pressurized with 100 psi of hydrogen gas and stirred for 28 hours
at 25.degree. C. to 60.degree. C. The reaction was filtered, and
the filtrate was rotary evaporated to give a thick oil.
Chromatography (20% ethyl acetate/hexanes, SiO.sub.2) of the oil
gave 12.2 (92%) of
4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl
ester as a clear oil. .sup.1H-NMR (CDCl.sub.3); .delta.7.85 (d,
2H), 7.70 (dd, 1H), 7.27 (m, 3H), 6.78 (m, 2H), 5.18 (bt, 1H), 4.82
(bs, 2H), 4.08 (d, 2H), and 1.57 (s, 9H). MS: M.sup.+=363.1 Da
[0750] Step (3): Synthesis of
4-[(2-Amino-5-bromo-benzenesulfonylamino)-me- thyl]-benzoic acid
tert-butyl ester 76
[0751] 4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid
tert-butyl ester (12.16 g, 33.5 mmol) was dissolved in 150 mL of
acetic acid at 10.degree. C. A solution of bromine (2.06 mL, 40.2
mmol) in 50 mL acetic acid was added dropwise. After complete
addition, a thick yellow precipitate was observed. The reaction was
filtered, and the solid washed with water. Chromatography of the
solid (20% ethyl acetate/hexanes, SiO.sub.2) gave 5.72 g (39%) of
4-[(2-Amino-5-bromo-benzenesulfonylamino)- -methyl]-benzoic acid
tert-butyl ester as a white solid. .sup.1H-NMR (CDCl.sub.3); 7.86
(d, 2H), 7.74 (d, 1H), 7.37 (dd, 1H), 7.23 (m, 2H), 6.65 (d, 1H),
5.19 (bt, 1H), 4.14 (d, 2H), and 1.58 (s, 9H). MS: M.sup.+=441.0
Da
[0752] Step (4): Synthesis of
4-(7-Bromo-1,1,3-trioxo-3,4-dihydro-1H-1.lam-
bda..sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid
tert-butyl ester 77
[0753] 4-[(2-Amino-5-bromo-benzenesulfonylamino)-methyl]-benzoic
acid tert-butyl ester. (3.72 g, 8.4 mmol) was dissolved in 150 mL
of tetrahydrofuran. Bis(trichloromethyl) carbonate (2.75 g, 9.3
mmol) was added followed by 0.8 mL (8.4 mmol) of pyridine. The
resulting suspension was stirred for 16 hours at room temperature.
The reaction was then partitioned between 1M HCl and ethyl acetate.
The organic layer was dried (magnesium sulfate), filtered, and
concentrated to give an oily solid. Chromatography (20% ethyl
acetate/hexanes, SiO.sub.2) gave 3.7 g (94%) of
4-(7-bromo-1,1,3-trioxo-3,4-dihydro-1H-1.lambda..sup.6-benzo[1,2,4]thiadi-
azin-2-ylmethyl)-benzoic acid tert-butyl ester as a white solid.
.sup.1H-NMR (CDCl.sub.3); .delta.9.49 (s, 1H), 7.94 (m, 3H), 7.64
(dd, 1H), 7.46 (d, 2H), 6.79 (d, 1H), 5.08 (s, 2H), and 1.55 (s,
9H). MS: M.sup.+=466.9 Da
[0754] Step (5): Synthesis of
4-[1,1,3-Trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-
-dihydro-1H-1.lambda..sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic
acid tert-butyl ester 78
[0755] When the procedure of Example 4, Step (4)
4-[6-iodo-1-methyl-2,4-di-
oxo-1,4-dihydro-2H-2.lambda..sup.4-benzo[1,2,6]thiadiazin-3yl
methyl)benzoic acid tert-butyl ester was replaced with
4-(7-bromo-1,1,3-trioxo-3,4-dihydro-1H-1.lambda..sup.6-benzo[1,2,4]thiadi-
azin-2-ylmethyl)-benzoic acid tert-butyl ester (0.38 g, 0.81 mmol),
0.18 g (44%) of
4-[1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1.lambda-
..sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid tert-butyl
ester was obtained as an off-white solid. .sup.1H-NMR (CDCl.sub.3);
.delta.8.99 (s, 1H), 7.92 (m, 3H), 7.57 (dd, 1H), 7.47 (d, 2H),
7.34 (m, 3H), 7.26 (m, 2H), 6.82 (d, 1H), 5.08 (s, 2H), 3.81 (s,
2H), and 1.54 (s, 9H). MS: M.sup.+-1=501.1 Da
[0756] Step (6): Synthesis of
4-[1,1,3-Trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-
-dihydro-1H-1.lambda..sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic
acid 79
[0757] When in the procedure of Example 4, Step (5)
4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2.lambda..s-
up.4-benzo[1,2,6]thiadiazin-3-yl methyl]benzoic acid tert-butyl
ester was replaced with
4-[1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1.l-
ambda..sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid
tert-butyl ester (0.12 g, 0.24 mmol) to give 0.9 g (84%) of
4-[1,1,3-trioxo-7-(3-phe-
nyl-prop-1-ynyl)-3,4-dihydro-1H-1.lambda..sup.6-benzo[1,2,4]thiadiazin-2-y-
lmethyl]-benzoic acid as a white solid. .sup.1H-NMR (CDCl.sub.3);
11.00 (s, 1H), 7.85 (d, 2H), 7.74 (s, 1H), 7.43 (d, 1H), 7.35 (d,
2H), 7.16 (m, 6H), 4.94 (s, 2H), and 3.70 (s, 2H). MS:
M.sup.++1=447.0 Da
EXAMPLE 18
2-(4-Methoxy-benzyl)-1,1-dioxo-7-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H,
1.lambda..sup.6-benzo[1,2,4]thiadiazin-3-one
[0758] Step (1): Synthesis of
N-(4-Methoxy-benzyl)-2-nitro-benzenesulfonam- ide 80
[0759] When in the procedure of Example 17, Step (1),
4-aminomethyl-benzoic acid tert-butyl ester was replaced with
4-methoxybenzlamine, the title compound
N-(4-methoxy-benzyl)-2-nitro-benz- enesulfonamide was obtained as a
yellow solid. .sup.1H-NMR (CDCl.sub.3); .delta.7.99 (dd, 1H), 7.80
(dd, 2H), 7.65 (m, 2H), 7.10 (d, 2H) 6.73 (d, 2H), 5.62 (bt, 1H),
4.23 (d, 2H), and 3.74 (s, 3H). MS: M.sup.+=322.0 Da
[0760] Step (2): Synthesis of
2-Amino-N-(4-methoxy-benzyl)-benzenesulfonam- ide 81
[0761] When in the procedure of Example 17, Step (2),
4-[(2-nitro-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl
ester was replaced with
N-(4-methoxy-benzyl)-2-nitro-benzenesulfonamide, the title compound
2-amino-N-(4-methoxy-benzyl)-benzenesulfonamide was obtained as a
thick oil. .sup.1H-NMR (CDCl.sub.3); .delta.7.71 (dd, 1H), 7.07 (d,
2H), 6.78 (m, 4H), 4.93 (bt, 1H), 4.82 (bs, 2H), 3.95 (d, 2H), and
3.75 (s, 3H). MS: M.sup.+-1=291.0 Da
[0762] Step (3): Synthesis of
2-Amino-5-bromo-N-(4-methoxy-benzyl)-benzene- sulfonamide 82
[0763] When in the procedure of Example 17, Step (3)
4-[(2-amino-benzenesulfonylamino)-benzoic acid tert-butyl ester was
replaced with 2-amino-N-(4-methoxy-benzyl)-benzenesulfonamide, the
title compound
2-amino-5-bromo-N-(4-methoxy-benzyl)-benzenesulfonamide was
obtained as a clear oil. .sup.1H-NMR (CDCl.sub.3); .delta.7.75 (s,
1H), 7.36 (d, 1H), 7.07 (d, 2H), 6.77 (d, 2H), 6.62 (d, 1H), 5.03
(bt, 1H), 4.85 (bs, 2H), 4.01 (d, 2H), and 3.76 (s, 3H). MS:
M.sup.+=371.0 Da
[0764] Step (4): Synthesis of
7-Bromo-2-(4-methoxy-benzyl)-1,1-dioxo-1,4-d-
ihydro-2H-1.lambda..sup.6-benzo[1,2,4]thiadiazin-3-one 83
[0765] When the procedure of Example 17, Step (4)
4-[(2-Amino-5-bromo-benz- enesulfonylamino)-methyl]-benzoic acid
tert-butyl ester was replaced with
2-amino-N-(4-methoxy-benzyl)-benzenesulfonamide, the title compound
7-bromo-2-(4-methoxy-benzyl)-1,1-dioxo-1,4-dihydro-2H-1.lambda..sup.6-ben-
zo[1,2,4]thiadiazin-3-one was obtained as an off-white solid.
.sup.1H-NMR (CDCl.sub.3); .delta.10.94 (s, 1H), 7.77 (s, 1H), 7.48
(dd, 1H), 7.27 (m, 2H), 7.03 (d, 1H), 6.71 (d, 2H), 4.86 (s, 2H),
and 3.66 (s, 3H). MS: M.sup.+=396.96 Da
[0766] Step (5): Synthesis of
2-(4-Methoxy-benzyl)-1,1-dioxo-7-(3-phenyl-p-
rop-1-ynyl)-1,4-dihydro-2H-1.lambda..sup.6-benzo[1,2,4]thiadiazin-3-one
84
[0767] When in the procedure of Example 15, Step (4),
4-[6-iodo-1-methyl-2,4-dioxo-1,4-dihydro-2H-2.lambda..sup.4-benzo[1,2,6]t-
hiadiazin-3yl methyl)benzoic acid tert-butyl ester was replaced
with
7-bromo-2-(4-methoxy-benzyl)-1,1-dioxo-1,4-dihydro-2H-1.lambda..sup.6-ben-
zo[1,2,4]thiadiazin-3-one, the title compound
2-(4-methoxy-benzyl)-1,1-dio-
xo-7-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-1.lambda..sup.6-benzo[1,2,4]thi-
adiazin-3-one was obtained as a yellow solid. .sup.1H-NMR
(CDCl.sub.3); .delta.8.99 (s, 1H), 7.92 (s, 1H), 7.58 (dd, 1H),
7.33 (m, 8H), 6.91 (d, 1H), 6.83 (d, 2H), 5.01 (s, 2H), 3.83 (s,
2H), and 3.76 (s, 3H). MS: M.sup.+-1=431.0 Da
EXAMPLE 19
4-[1,1,3-Trioxo-7-(4-phenyl-but-1-ynyl)-3,4-dihydro-1H-1.lambda..sup.6
-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid
[0768] Step (1): Synthesis of
4-[1,1,3-Trioxo-7-(4-phenyl-but-1-ynyl)-3,4--
dihydro-1H-1.lambda..sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic
acid tert-butyl ester 85
[0769] When in the procedure of Example 15, Step (4),
3-phenyl-1-propyne was replaced with 4-phenyl-1-butyne, the title
compound
4-[1,1,3-trioxo-7-(4-phenyl-but-1-ynyl)-3,4-dihydro-1H-1.lambda..sup.6-be-
nzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid tert-butyl ester was
obtained as an off-white solid. .sup.1H-NMR (CDCl.sub.3);
.delta.9.08 (s, 1H), 7.94 (d, 2H), 7.81 (s, 1H), 7.52 (m, 3H), 7.28
(m, 5H), 6.81 (d, 1H), 5.08 (s, 2H), 2.92 (t, 2H) 2.71 (t, 2H), and
1.57 (s, 9H). MS: M.sup.+-1=515.2 Da
[0770] Step (2): Synthesis of
4-[1,1,3-Trioxo-7-(4-phenyl-but-1-ynyl)-3,4--
dihydro-1H-1.lambda..sup.6
benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid 86
[0771] When in procedure of Example 15, Step (5),
4-[1-methyl-2,4-dioxo-6--
(3-phenyl-prop-1-ynyl-1,4-dihydro-2H-2.lambda..sup.4-benzo[1,2,6]thiadiazi-
n-3-yl methyl]benzoic acid tert-butyl ester was replaced with
4-[1,1,3-trioxo-7-(4-phenyl-but-1-ynyl)-3,4-dihydro-1H-1.lambda..sup.6-be-
nzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid tert-butyl ester, the
title compound
4-[1,1,3-trioxo-7-(4-phenyl-but-1-ynyl)-3,4-dihydro-1H-1.lambda.-
.sup.6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid was obtained
as a white solid. .sup.1H-NMR (CDCl.sub.3); .delta.10.95 (s, 1H),
7.90 (d, 2H), 7.69 (s, 1H), 7.39 (m, 3H), 7.16 (m, 7H), 4.98 (s,
2H), 2.82 (t, 2H), and 2.60 (t, 2H). MS: M.sup.++1=461.0 Da
[0772] The invention compounds of Formula I have been evaluated in
standard assays for their ability to inhibit the activity of
various MMP enzymes. The assays used to evaluate the biological
activity of the invention compounds are well-known and routinely
used by those skilled in the study of MMP inhibitors and their use
to treat clinical conditions.
[0773] The assays measure the amount by which a test compound
reduces the hydrolysis of a thiopeptolide substrate caused by a
matrix metalloproteinase enzyme. Such assays are described in
detail by Ye et al., in Biochemistry, 1992;31(45):11231-11235,
which is incorporated herein by reference.
[0774] Thiopeptolide substrates show virtually no decomposition or
hydrolysis in the absence of a matrix metalloproteinase enzyme. A
typical thiopeptolide substrate commonly utilized for assays is
Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt. A 100 .mu.L assay mixture
will contain 50 mM of 2-morpholinoethane sulfonic acid monohydrate
(MES, pH 6.0) 10 mM CaCl.sub.2, 100 .mu.M thiopeptolide substrate,
and 1 mM 5,5'-dithio-bis-(2-nitro-benzoic acid) (DTNB). The
thiopeptolide substrate concentration is varied from 10 to 800
.mu.M to obtain Km and Kcat values. The change in absorbance at 405
nm is monitored on a Thermo Max microplate reader (molecular
Devices, Menlo Park, Calif.) at room temperature (22.degree. C.).
The calculation of the amount of hydrolysis of the thiopeptolide
substrate is based on E.sub.412=13600 m.sup.-1 cm.sup.-1 for the
DTNB-derived product 3-carboxy-4-nitrothiophenoxide. Assays are
carried out with and without matrix metalloproteinase inhibitor
compounds, and the amount of hydrolysis is compared for a
determination of inhibitory activity of the test compounds.
[0775] Several representative compounds have been evaluated for
their ability to inhibit various matrix metalloproteinase enzymes.
Table 1 below presents inhibitory activity as IC.sub.50's in
micromolar for representative invention compounds. In the table,
MMP-1FL refers to full length interstitial collagenase; MMP-2FL
refers to full length Gelatinase A; MMP-3CD refers to the catalytic
domain of stromelysin; MMP-7FL refers to full length matrilysin;
MMP-9FL refers to full length Gelatinase B; MMP-13CD refers to the
catalytic domain of collagenase 3; and MMP-14CD refers to the
catalytic domain of MMP-14. Test compounds were evaluated at
various concentrations in order to determine their respective
IC.sub.50 values, the micromolar concentration of compound required
to cause a 50% inhibition of the hydrolytic activity of the
respective enzyme.
1TABLE 1 IC.sub.50 (.mu.M) Versus MMPs Example MMP01 MMP02 MMP02
MMP03 MMP07 MMP09 MMP13 MMP14 No. (FL) (CD) (FL) (CD) (FL) (FL)
(CD) (CD) 1 N/A.sup.a N/A N/A N/A N/A N/A 2.2 N/A 2 N/A N/A N/A N/A
N/A N/A 0.0042 N/A .sup.aN/A means datum is not available.
[0776] The ability of the compounds of Examples 4 to 6 to inhibit
the catalytic activity of MMP-13 CD is shown below in Table 2 in
the column labeled "MMP-13CD (IC.sub.50, .mu.M)", wherein the
activity is expressed as IC.sub.50's in micromolar concentration of
compound.
2 TABLE 2 Example No. MMP-13CD (IC.sub.50, .mu.M) 4 100 5 66 6
0.029
[0777] The abilities of the compounds of Examples 1 to 3 and 15 to
19 to inhibit the catalytic activity of MMP-13 CD, as well as the
abilities of the compounds of Examples 1 to 3 and 15 to 18 to
inhibit full-length MMP01, full-length MMP02, MMP03 catalytic
domain, full-length MMP07, full-length MMP09, and MMP-14 catalytic
domain, is shown below in Table 3 in the columns labeled "MMP-13
(CD)", and "MMP01 (FL)", "MMP02 (FL)", "MMP03 (CD)", "MMP07 (FL)",
"MMP09 (FL)", and "MMP14 (CD)", respectively. In Table 3, the
inhibitory activities are expressed as IC.sub.50's in micromolar
concentration of compound.
3TABLE 3 IC.sub.50 (.mu.M) Example MMP01 MMP02 MMP03 MMP07 MMP09
MMP13 MMP14 No. (FL) (FL) (CD) (FL) (FL) (CD) (CD) 1 >100 >30
>30 >30 >100 2.2 >100 2 >30 >30 >10 >30
>30 0.0042 >30 3 >30 >100 >30 >30 >30 0.12
>30 15 >30 >30 >10 24 >100 0.01045 >30 16 >30
>30 12 >30 >30 0.0315 >30 17 >30 >100 5.6 16
>100 0.005167 >30 18 >30 >30 >30 >10 >30 0.185
>30 19 0.079
[0778] The foregoing data establish that the invention compounds of
Formula I are potent inhibitors of MMP enzymes, and are especially
useful due to their selective inhibition of MMP-13. Because of this
potent and selective inhibitory activity, the invention compounds
are especially useful to treat diseases mediated by the MMP
enzymes, and particularly those mediated by MMP-13.
[0779] The compounds of the present invention can be prepared and
administered in a wide variety of oral and parenteral dosage forms.
Thus, the compounds of the present invention can be administered by
injection, that is, intravenously, intramuscularly,
intracutaneously, subcutaneously, intraduodenally, ,or
intraperitoneally. Also, the compounds of the present invention can
be administered by inhalation, for example, intranasally.
Additionally, the compounds of the present invention can be
administered transdermally. It will be obvious to those skilled in
the art that the following dosage forms may comprise as the active
component, either a compound of Formula I, or a corresponding
pharmaceutically acceptable salt of a compound of Formula I. The
active compound generally is present in a concentration of about 5%
to about 95% by weight of the formulation.
[0780] For preparing pharmaceutical compositions from the compounds
of the present invention, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. A solid carrier can be one or more substances which may
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
[0781] In powders, the carrier is a finely divided solid that is in
a mixture with the finely divided active component.
[0782] In tablets, the active component is mixed with the carrier
having the necessary binding properties in suitable proportions and
compacted in the shape and size desired.
[0783] The powders and tablets preferably contain from 5% or 10% to
about 70% of the active compound. Suitable carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation
of the active compound with encapsulating material as a carrier
providing a capsule in which the active component, with or without
other carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid dosage forms suitable for oral administration.
[0784] For preparing suppositories, a low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to
solidify.
[0785] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water propylene glycol solutions.
For parenteral injection, liquid preparations can be formulated in
solution in aqueous polyethylene glycol solution.
[0786] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavors, stabilizing, and thickening agents as
desired.
[0787] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other
well-known suspending agents.
[0788] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[0789] The pharmaceutical preparation is preferably in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets,
capsules, and powders in vials or ampoules. Also, the unit dosage
form can be a capsule, tablet, cachet, or lozenge itself, or it can
be the appropriate number of any of these in packaged form.
[0790] The quantity of active component in a unit dose preparation
may be varied or adjusted from 1 to 1000 mg, preferably 10 to 100
mg according to the particular application and the potency of the
active component. The composition can, if desired, also contain
other compatible therapeutic agents.
[0791] In therapeutic use as agents to inhibit a matrix
metalloproteinase enzyme for the treatment of atherosclerotic
plaque rupture, aortic aneurism, heart failure, restenosis,
periodontal disease, corneal ulceration, cancer metastasis, tumor
angiogenesis, arthritis, or other autoimmune or inflammatory
disorders dependent upon breakdown of connective tissue, the
compounds utilized in the pharmaceutical method of this invention
are administered at a dose that is effective to inhibit the
hydrolytic activity of one or more matrix metalloproteinase
enzymes. The initial dosage of about 1 mg/kg to about 100 mg/kg
daily will be effective. A daily dose range of about 25 mg/kg to
about 75 mg/kg is preferred. The dosages, however, may be varied
depending upon the requirements of the patient, the severity of the
condition being treated, and the compound being employed.
Determination of the proper dosage for a particular situation is
within the skill of the art. Generally, treatment is initiated with
smaller dosages that are less than the optimum dose of the
compound. Thereafter, the dosage is increased by small increments
until the optimum effect under the circumstance is reached. For
convenience, the total daily dosage may be divided and administered
in portions during the day if desired. Typical dosages will be from
about 0.1 mg/kg to about 500 mg/kg, and ideally about 25 mg/kg to
about 250 mg/kg, such that it will be an amount that is effective
to treat the particular disease being prevented or controlled.
[0792] The following examples illustrate typical formulations
provided by the invention.
Formulation Example 1
[0793]
4 Tablet Formulation Ingredient Amount (mg) Compound of Example 3
25 Lactose 50 Corn starch (for mix) 10 Corn starch (paste) 10
Magnesium stearate (1%) 5 Total 100
[0794] The alkyne of Example 3, lactose, and corn starch (for mix)
are blended to uniformity. The corn starch (for paste) is suspended
in 200 mL of water and heated with stirring to form a paste. The
paste is used to granulate the mixed powders. The wet granules are
passed through a No. 8 hand screen and dried at 80.degree. C. The
dry granules are lubricated with the 1% magnesium stearate and
pressed into a tablet. Such tablets can be administered to a human
from one to four times a day for treatment of atherosclerosis and
arthritis. Formulation Example 2
5 Preparation for Oral Solution Ingredient Amount Compound of
Example 1 400 mg Sorbitol solution (70% N.F.) 40 mL Sodium benzoate
20 mg Saccharin 5 mg Red dye 10 mg Cherry flavor 20 mg Distilled
water q.s. 100 mL
[0795] The sorbitol solution is added to 40 mL of distilled water,
and the alkyne of Example 1 is dissolved therein. The saccharin,
sodium benzoate, flavor, and dye are added and dissolved. The
volume is adjusted to 100 mL with distilled water. Each milliliter
of syrup contains 4 mg of invention compound.
Formulation Example 3
[0796] Parenteral Solution
[0797] In a solution of 700 mL of propylene glycol and 200 mL of
water for injection is suspended 20 g of the compound of Example 2.
After suspension is complete, the pH is adjusted to 6.5 with 1N
sodium hydroxide, and the volume is made up to 1000 mL with water
for injection. The formulation is sterilized, filled into 5.0-mL
ampoules each containing 2.0 mL, and sealed under nitrogen.
[0798] As matrix metalloproteinase inhibitors, the compounds of
Formula I are useful as agents for the treatment of multiple
sclerosis. They are also useful as agents for the treatment of
atherosclerotic plaque rupture, restenosis, periodontal disease,
corneal ulceration, treatment of burns, decubital ulcers, wound
repair, heart failure, cancer metastasis, tumor angiogenesis,
arthritis, and other inflammatory disorders dependent upon tissue
invasion by leukocytes.
* * * * *